Young Children with Attention-Deficit/Hyperactivity Disorder and/or Disruptive Behavior Disorders Are More Frequently Prescribed Alpha Agonists Than Stimulants

Abstract

Objective:

To examine medication prescribing patterns for preschool-aged children with diagnoses of attention-deficit/hyperactivity disorder (ADHD) and/or disruptive behavior disorder (DBD). Secondary objectives included determining if prescription patterns varied by gender, insurance type, or comorbid diagnosis of autism spectrum disorder (ASD).

Methods:

A retrospective, cross-sectional chart review was completed for children ages 2–5 years who were treated at an academic medical center between 2013 and 2016 with a diagnosis of ADHD and/or DBD. Data were analyzed by Fisher's exact and chi-square tests and Cochran–Armitage trend analysis.

Results:

Of the 966 children who met inclusion criteria, 343 (35.5%) were prescribed ADHD medications. For 2-, 3-, and 4-year olds, the most commonly prescribed medication was an alpha agonist (AA), while for 5-year olds, methylphenidate (MPH) was most commonly prescribed. With advancing age, an increasing number of children were prescribed a stimulant medication and a decreasing number of children were prescribed an AA (p < 0.001). Children were more often prescribed an MPH formulation (48.2%) compared with amphetamine-based stimulants (26.8%). Children without ASD were more likely to be prescribed a stimulant medication (72.1%) when compared with children with ASD (37.0%, p < 0.0001). Children with private insurance were more likely to be prescribed an extended-release stimulant medication when compared with Medicaid patients (34.3% vs. 17.2%, p = 0.004).

Conclusion:

Both stimulants and nonstimulants are being prescribed regularly in very young children, even before the age of four at an academic medical center. AAs were the most commonly prescribed medication for children 2, 3, and 4 years of age with diagnoses of ADHD, DBD, and ASD. Insurance type, comorbid diagnosis of ASD, and age of child were found to be significantly associated with prescribing a nonpreferred medication.

Introduction

Although most cases of attention-deficit/hyperactivity disorder (ADHD) are diagnosed when children are school age (Visser et al. 2014), symptoms of ADHD often cause significant functional impairment before the age of 6. The prevalence of ADHD in preschool-aged children ranges from 0.9% to 4% (Thomas et al. 2015), and ∼40% of 4- and 5-year olds diagnosed with ADHD receive the diagnosis before the age of 4. In preschool-aged children with ADHD, impulsivity and hyperactivity manifest as severe temper tantrums, elopement behavior, and aggressiveness. These symptoms can lead to safety concerns and consequences, such as expulsion from preschool or childcare. Treatment of ADHD during early childhood has the potential to stave off the functional impairment so commonly associated with ADHD throughout the life span.

The diagnosis of ADHD in preschool-aged children can be difficult. Children may be given a primary or comorbid diagnosis of oppositional defiant disorder, disruptive behavior disorder (DBD), or conduct disorder. The first guidelines for management of preschool behavioral disorders were published in 2007 by the American Academy of Child and Adolescent Psychiatry (AACAP) (Gleason et al. 2007). In 2011, the American Academy of Pediatrics (AAP) published updated clinical guidelines to include management of preschool-aged children with ADHD (Subcommittee on Attention-Deficit/Hyperactivity Disorder 2011). Both clinical practice guidelines recommend evidence-based behavioral therapy as the first-line intervention, before medications, for preschool-aged children with ADHD and DBD. These behavioral programs target the disruptive behaviors that typically accompany ADHD and DBD in young children by teaching parents behavior management strategies that are based on the principles of positive reinforcement (Charach et al. 2011).

Although behavioral therapy is the recommended first-line treatment for preschoolers with ADHD and DBD, for those children who exhibit “moderate-to-severe dysfunction” or in locations where evidence-based behavioral treatment is not available, medications may be considered (Subcommittee on Attention-Deficit/Hyperactivity Disorder 2011). According to the criteria used by the Preschool Attention-Deficit/Hyperactivity Treatment Study (PATS) (Greenhill et al. 2006), moderate-to-severe dysfunction is defined as symptoms persisting for at least 9 months, dysfunction manifested in several settings (home, preschool, or childcare facility), and dysfunction that has not responded to behavioral therapy (Subcommittee on Attention-Deficit/Hyperactivity Disorder 2011).

The AAP guidelines (Subcommittee on Attention-Deficit/Hyperactivity Disorder 2011) for medication treatment of ADHD in preschool-aged children recommend medication initiation with methylphenidate immediate-release (MPH IR). MPH IR has moderate evidence in support of efficacy and safety in preschool-aged children, largely supported by the PATS (Greenhill et al. 2006). However, MPH IR is not FDA approved for children younger than 6 years and is considered off-label use for preschool-aged children with ADHD. The only FDA-approved medications for children younger than 6 years are amphetamine-based stimulants, approved in 1946, perhaps when regulations were less stringent (Bradley 1950; Barkley 1977; Angell 2008).

Although the AACAP guidelines do recommend amphetamines if methylphenidate (MPH) is not tolerated, there is little evidence supporting its use in children younger than 6 years (Gleason et al. 2007). Nonstimulant medications are also used for the treatment of ADHD, specifically alpha agonists (AAs) and atomoxetine, but are not recommended as monotherapy or as adjunctive therapy in preschool ADHD or DBD (Danielson et al. 2017). Interestingly, no extended-release (ER) medication, nonstimulant or stimulant, is approved for children younger than 6 years, despite being the preferred formulation for older children with better medication adherence (compliance decreases with multiple doses each day) (Swanson 2005; Cascade et al. 2008; Feldman and Bélanger 2009).

With regard to psychotropic treatment for children with DBD, data are even more limited. In children with DBD without co-occurring ADHD, atypical antipsychotics are recommended by AACAP as first- line treatment (Gleason et al. 2007). Data examining psychotropic medications prescribed in preschool-aged children with DBD without co-occurring ADHD are limited. While atypical antipsychotics are recommended by AACAP as first-line medication treatment for children with DBD without co-occurring ADHD, these medications can have severe long-term side effects.

Physician prescribing practices may be influenced by a variety of factors, although this is not well studied. Comorbidities may play a role in medication choice. Comorbidities, such as autism spectrum disorder (ASD) or sleep difficulties, may influence a practitioner's decision to start an AA. Several previous studies have found a correlation between number of comorbidities and likelihood of medication initiation. Blum and colleagues found both stimulants and AAs were both prescribed more frequently in children with comorbid conditions (Blum et al. 2018). In the same study, children with sleep difficulties were more likely to be prescribed AAs, while children with speech disorders and disruptive behavior were more likely to be prescribed a stimulant medication. Fik and colleagues reported that 27% of preschool-aged children with ADHD had a comorbid diagnosis, but more research is needed examining prescribing trends in young children with moderate dysfunction due to ADHD to better serve this already vulnerable population (Fiks et al. 2016).

The primary objective of this study was to determine medication prescribing trends for preschool-aged children with a diagnosis of ADHD and/or DBD at an academic medical center. Secondary objectives included determining if prescription patterns varied by gender, insurance type, or comorbid diagnosis of ASD.

Methods

Participants

Inclusion criteria consisted of children ages 2–5 years who were treated at an academic medical center over a 3-year period (between July 1, 2013, and July 1, 2016) with a diagnosis of ADHD and/or DBD. These diagnoses were included to ensure that children who were prescribed ADHD medications for impairing behaviors, but possibly subthreshold for diagnosis of ADHD, were captured in the data set. International Classification of Diseases (ICD)-9 and ICD-10 codes were included since ICD-10's compliance date did not begin until October 1, 2014.

The following codes were included as part of data extraction: ICD-10 codes: F90.0 (Attention-Deficit/Hyperactivity Disorder—Predominantly Inattentive Type), F90.1 (Attention-Deficit/Hyperactivity Disorder—Predominantly Hyperactive Type), F90.2 (Attention-Deficit/Hyperactivity Disorder—Combined Type), F90.8 (Attention-Deficit/Hyperactivity Disorder—Other Type), F 90.9 (Attention-Deficit/Hyperactivity Disorder, Unspecified Type), F91.9 (Conduct Disorder-Deficit/Hyperactivity Disorder—Unspecified Type), F91.9, F91.3 (Oppositional Defiant Disorder), F93.9 (Childhood Emotional Disorder, Unspecified), and F91.8 (Other Conduct Disorders); ICD-9 codes of 314.0 (Attention-Deficit Disorder of Childhood), 314.01(Attention-Deficit Disorder with Hyperactivity), 314.00 (Attention-Deficit Disorder with Inattention), 314.8 (Attention-Deficit Disorder, Residual Type), 312.89 (Other Conduct Disorder), 312.9 (Unspecified Disturbance of Conduct), 314.1 (Hyperkinesis with Developmental Delay), 314.2 (Hyperkinesis with Conduct Disorder), 314.9 (Unspecified Hyperkinetic Syndrome), and 313.81 (Oppositional Defiant Disorder). ICD 9 codes for hyperkinesis were included since this diagnosis was previously used to describe severe impairment due to hyperactivity, inattention, and impulsivity but was replaced by ADHD, combined type.

The following departments prescribing medications of interest to preschool-aged children were included: developmental-behavioral pediatrics, outpatient child psychiatry, inpatient child psychiatry, general pediatrics, and pediatric neurology.

Data extraction

Deidentified data were extracted from the electronic health record (EHR) through a web-based research management system that provides a central portal for researchers at our institution. The following information was collected from the EHR: (1) age of the child associated with visit, (2) medications of interest: all psychotropic medications prescribed (ADHD medications, selective serotonin reuptake inhibitors [SSRIs], neuroleptics, as well as melatonin), (3) medication start dates, (4) primary diagnosis and all secondary diagnoses, and (5) demographic information, including ethnicity, gender, and insurance type. Children could have greater than one diagnosis at time of visit encounter. Insurance type was subcategorized as Medicaid, private insurance, and unknown.

For analytic purposes, patients with multiple prescriptions were set as unique patients by age of first medication prescription. Medications prescribed after the child advanced to the next age category were excluded from analysis. Stimulant medications were divided into the following categories: amphetamine based salts extended-release (ABS ER), amphetamine based salts immediate-release (ABS IR), methylphenidate extended-release (MPH ER), and MPH IR. Concerta^®, Focalin XR^®, Metadate^® CD, Ritalin LA^®, and Quillivant XR^® comprised the medications in the MPH ER group. Adderall XR^® and Vyvanse^® comprised the medications in the ABS ER group. No children were prescribed Dexedrine SR. This was done to capture prescribing trends of ER medications versus immediate-release (IR) formulations, and to differentiate between classes of stimulant.

Nonstimulant medications included in the analyses were guanfacine IR (Tenex^®), guanfacine ER (Intuniv^®), and clonidine IR, and all three comprised the AA group. No child was prescribed clonidine ER (Kapvay^®), Strattera^®, Wellbutrin^®, or the clonidine patch, and therefore was not included in any group analysis. Information regarding other medications of interest included SSRIs, melatonin, and antipsychotic medications and also was extracted from the medical record.

All disruptive behavior/conduct disorder codes were grouped together for analysis, and all hyperkinesis diagnosis were grouped together for analysis. Demographic and prescribed medication characteristics were presented descriptively. Medications were compared by gender, comorbid conditions, and insurance type using Fisher's exact and chi-square tests. Medications were also compared by age with Cochran–Armitage exact trend tests with Bonferroni-defined significance threshold of p < 0.0056. All analyses were conducted in SAS v9.4 (SAS, Inc., Cary, NC).

Results

Participant characteristics

Data extraction yielded 966 children who met the inclusion criteria, including a diagnosis of interest. Patient demographic characteristics are in Table 1. For the entire sample, irrespective of medication prescribed, 470 (48.7%) had received a diagnosis of ADHD, 93 (9.6%) had received a diagnosis of hyperkinesis not otherwise specified (NOS), 388 (40.2%) had received a diagnosis of DBD/conduct disorder NOS, and 15 (1.6%) had received a diagnosis of oppositional defiant disorder. A total of 105 (10.9%) children had received a comorbid diagnosis of ASD. Seven percent of children had a comorbid sleep disorder. Children may have had one or more diagnoses at time of visit encounter.

Table 1.

Patient Demographic Characteristics

	All patients (n = 966)	On medication (n = 343)
	n (%)	n (%)
Age
2 years	69 (7.1)	2 (0.7)
3 years	149 (15.4)	26 (7.5)
4 years	296 (30.6)	108 (31.5)
5 years	452 (46.8)	207 (60.3)
Gender
Male	710 (73.5)	262 (76.4)
Female	256 (26.5)	81 (23.6)
Insurance type
Private	122 (12.6)	70 (20.4)
Public	303 (31.4)	169 (49.3)
Unknown	541 (56.0)	104 (30.2)
Ethnicity
Black	386 (43.8)	168 (49.2)
White	477 (54.1)	168 (49.2)
Hispanic	13 (1.5)	5 (1.5)
Other	5 (0.6)	2 (0.5)
Diagnosis
ADHD	470 (48.7)	194 (56.56)
Disruptive behavior disorder	351 (36.3)	111 (32.36)
Hyperkinesis NOS	82 (8.5)	35 (10.20)
Oppositional defiant disorder	15 (1.6)	3 (0.87)
Comorbid autism spectrum disorder	48 (5.0)	46 (13.41)

ADHD, attention-deficit/hyperactivity disorder; n, frequency; NOS, not otherwise specified.

Treatment characteristics

A total of 343 (35.5%) children ages 2–5 were prescribed an ADHD medication, of which 32.7% were prescribed an AA and 46.1% a stimulant; 21.3% were prescribed both an AA and stimulant during the year of medication initiation, either by discontinuing one and starting another or simultaneously. The percentage of children in each age group prescribed ADHD medication is shown in Table 2.

Table 2.

Prescription Patterns by Age at Initial Treatment (n = 343)

	Total, n (%)	Age, n (%)
	Total, n (%)	2-year olds	3-year olds	4-year olds	5-year olds	Age trend
	n = 343	n = 2	n = 26	n = 108	n = 207	p-Value
MPH
IR	139 (40.5)	0 (0.0)	1 (3.9)	41 (38.0)	97 (46.9)	<0.0001
ER	58 (16.9)	0 (0.0)	0 (0.0)	12 (11.1)	46 (22.2)	0.0004
Total	166 (48.4)	0 (0.0)	1 (3.9)	48 (44.4)	117 (56.5)	<0.0001
ABS
IR	76 (22.2)	0 (0.0)	1 (3.9)	18 (16.7)	57 (27.5)	0.0011
ER	32 (9.3)	0 (0.0)	0 (0.00)	3 (2.8)	29 (14.0)	0.0008
Total	92 (26.8)	0 (0.0)	1 (3.85)	19 (17.6)	72 (34.8)	<0.0001
Alpha agonists
IR	182 (53.1)	2 (100)	26 (100)	80 (74.1)	74 (35.6)	<0.0001
ER	9 (2.6)	0 (0.0)	0 (0.00)	2 (1.9)	7 (3.4)	0.3116
Total	185 (53.9)	2 (100)	26 (100)	81 (75.0)	76 (36.7)	<0.0001

ABS, amphetamine based salts; ER, extended-release; IR, immediate release; MPH, methylphenidate; n, frequency.

For 2-, 3-, and 4-year olds, the most commonly prescribed medication was an AA, while for 5-year olds, the most commonly prescribed medication was a stimulant. As children got older, there were an increasing proportion of children prescribed a stimulant medication. There were a decreasing proportion of children prescribed an AA between the ages of 2 and 5 years (p < 0.001).

Children were more often prescribed an MPH formulation (48.4%) compared with amphetamine-based stimulants (ABS, 26.8%). Of the 46 children with a comorbid diagnosis of ASD initiated on medication, 37 (80.4%) were treated with an AA and 17 (37.0%) were treated with a stimulant. Children without ASD were more likely to be prescribed a stimulant medication (72.1%) when compared with children with ASD (37.0%) (p < 0.0001). A total of 6.1% of children with a comorbid sleep disorder were treated with an AA. Males were more likely to be prescribed a long acting stimulant when compared with females (27.9% vs. 16.1%, p = 0.032).

Children with private insurance were more likely to be prescribed an ER stimulant medication when compared with children with Medicaid (34.3% vs. 17.2%, p = 0.004)), specifically MPH ER (private 28.6%, Medicaid 11.2%, p = 0.001). Children with Medicaid were more likely to be prescribed ABS IR when compared with children with private insurance (private 14.3%, Medicaid 27.2%, p = 0.032). There was no difference in prescribing patterns for race (data not shown).

Other medications of interest included SSRIs, melatonin, and antipsychotic medications. Four 5-year olds were prescribed an SSRI. Antipsychotics were prescribed to one 3-year old, one 4-year old, and four 5-year olds. Melatonin was prescribed to twenty-four 5-year olds, seventeen 4-year olds, four 3-year olds, and one 2-year old.

Discussion

Since 2007–2008, the number of preschool-aged children diagnosed with ADHD has more than doubled (Danielson et al. 2017). According to the National Survey of Children's Health parent report, 39.6% of 4- and 5-year olds diagnosed with ADHD received the diagnosis before they turned 4 (Visser et al. 2014).

The results of this retrospective cross-sectional chart review found that 35.5% of preschool-aged children treated at an academic medical center received a diagnosis of ADHD and/or DBD and were prescribed an ADHD medication. Our rates are similar to the national trends in psychotropic medication use for young children that report a psychotropic medication prescription rate of 35.89% for preschool-aged children with any behavioral diagnosis (Chirdkiatgumchai et al. 2013).

A key finding of our study revealed that among preschool-aged children prescribed psychotropic medications, 26.8% were treated with amphetamine stimulants compared with 48.4% prescribed MPH-based formulations. No study to date has differentiated the different types of stimulant medications in preschool-aged children. The differentiation is important because only MPH IR, not ABS, has supporting evidence and recommendations for use in young children (Subcommittee on Attention-Deficit/Hyperactivity Disorder 2011). However, only ABS is FDA approved for use in children between 3 and 6 years of age. In addition, no study to our knowledge has examined the prevalence of ER medications in preschool-aged children (Visser et al. 2014).

Off-label use of medications is common practice in the pediatric population (Wilson 1999) and has long been an area of concern for pediatricians. The term “therapeutic orphan” was conceived in the 1960s to describe the lack of studies examining medications used in children and the dilemma of pediatric labeling (Wilson 1999). To gain FDA approval, the FDA requires at least two positive adequate and well-controlled clinical investigations or a large amount of evidence demonstrating the safety and efficacy in adults before conducting studies in children. When clinical trials are most often sponsored by the pharmaceutical industry, it is not cost-effective for them to reconduct a study in the pediatric population (Angell 2008).

Simply put, clinical trials in children, the basis of evidence-based medicine, are far and few between. In the realm of ADHD medications, preschool-aged children are perhaps the most vulnerable “therapeutic orphans.” This study highlights the urgent need for well-controlled studies examining their use in preschool-aged children.

The lack of clinical trials for children has resulted in many pediatric guidelines that are derived from expert opinion. The AAP guidelines for preschool-aged children with ADHD state that there is insufficient evidence to recommend dextroamphetamine, (Subcommittee on Attention-Deficit/Hyperactivity Disorder 2011), but no statement regarding AA or ER stimulant medication use is made. The AACAP consensus guidelines, lesser known by pediatricians, recommend that AAs or atomoxetine be tried if stimulants are ineffective or result in intolerable side effects (Gleason et al. 2007).

In our study, AAs were the most commonly prescribed medications for 2-, 3-, and 4-year olds. A recent national profile of preschoolers being treated for ADHD found that 33.5% of children were prescribed a nonstimulant medication, 21.7% of whom were prescribed an AA (clonidine or guanfacine) (Danielson et al. 2017). A study conducted by Fiks and colleagues utilizing EHR data from 63 primary care practices found that 21% of preschool-aged children were prescribed an AA in conjunction with a stimulant (Fiks et al. 2016).

A study examining prescribing practices among child and adolescent psychiatrists treating preschool-aged children diagnosed with ADHD found that 35.7% “typically chose” a medication other than MPH first, with 14.9% choosing a nonstimulant first (Jaeah et al. 2016). Although research has found that preschoolers experience more side effects when prescribed stimulants compared with older children, we can only hypothesize why practitioners are prescribing AAs so commonly in very young children without supportive evidence.

Clinically, families are often apprehensive about the use of stimulants due to the stigma associated with this classification of medication. Comorbidities, such as ASD or sleep difficulties, may also influence a practitioner's decision to start an AA. In our study, children with a comorbid diagnosis of ASD were more likely to be prescribed an AA when compared with children without a comorbid diagnosis of ASD. A recent study of three developmental/behavioral pediatric sites also found that AAs were used commonly in children with ASD (Jackel et al. 2017). Studies have shown a slightly increased rate of side effects in children with ASD prescribed stimulant medications (Nickels et al. 2008; DeFilippis and Wagner 2016), which may play a role in physician preference. Children with ADHD as well as ASD are known to be at increased risk for sleeping difficulties (Hvolby 2015). While stimulants can cause or exacerbate sleep initiation difficulties, AAs can help and may be a factor in medication selection.

The results of this retrospective cross-sectional chart review must be considered within the limitations of study design. This study was based on data extracted from the EMR, a strength when compared with most other published data on medication trends in preschoolers that utilized parent report. However, this method of data recovery did not gather information regarding reasons for medication initiation, discontinuation due to side effects, or combination medications versus monotherapy. While our method of data extraction allowed us to confirm accurately and specifically what medications were prescribed and observe general trends in medication prescribing practices, we could not confirm medication compliance.

Another limitation of our study is incomplete demographic information; the EHR was unable to extract insurance status in 56% of the sample, so conclusions regarding private versus public insurance should be interpreted with caution. In addition, data were only extracted for a single site, thus limiting the generalization of findings in other geographic regions. However, the general trends we have observed in prescribing practices at our institution correlate with other studies and contribute to supporting evidence that AAs are frequently used in young children with DBDs.

Conclusions

The number of preschool-aged children being diagnosed with ADHD has increased, and although there are treatment guidelines, our study highlights frequent use of medications not supported by present evidence-based guidelines. Both stimulants and nonstimulants are being prescribed regularly in very young children, even before the age of 4. At our institution, AAs were the most commonly prescribed medication for children 2, 3, and 4 years of age. There is a need for well-designed studies to improve evidence-based guidelines for the treatment of ADHD in preschool-aged children, and to assess the efficacy of stimulant and nonstimulant medication, severity of side effects, long-term outcomes, and impact on the developing brain.

Clinical Significance

There is a physician prescribing trend of frequent AA use in preschool-aged children with ADHD and DBDs. Physicians are prescribing AAs more frequently than stimulants in children 2, 3, and 4 years of age, in preschool-aged children, and also in children with a comorbid diagnosis of ASD.

Disclosures

The authors have indicated that they have no potential conflicts of interest to disclose, including any corporate/commercial relationships. The authors have no relationships with any pharmaceutical company and were not supported by a pharmaceutical company.

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