Association of Coexisting Conditions,Attention-Deficit/Hyperactivity Disorder Medication Choice,and Likelihood of Improvement in Preschool-Age Children: A Developmental Behavioral Pediatrics Research Network Study

Abstract

Objectives:

To determine whether conditions coexisting with attention-deficit/hyperactivity disorder (ADHD) in preschool-age children are associated with choice of stimulants or alpha-2 adrenergic agonists (A2As) and/or likelihood of improvement in ADHD symptoms.

Methods:

A retrospective electronic health record review of 497 children from 7 Developmental Behavioral Pediatrics Research Network (DBPNet) sites. Children were <72 months when treated with medication for ADHD from January 1, 2013 to July 1, 2017. We abstracted coexisting conditions, initial medication prescribed, and whether the medication was associated with improvement in symptoms. Analysis of improvement was adjusted for clustering by clinician and site.

Results:

The median (interquartile range) child age at the time of initiation of ADHD medication was 62 (54–67) months. The most common coexisting conditions included language disorders (40%), sleep disorders (28%), disruptive behavior disorders (22.7%), autism spectrum disorder (ASD; 21.8%), and motor disorders (19.9%). No coexisting conditions were present in 17.1%; 1 in 36.8%, 2 in 26.8%, and ≥3 in 19.3%. Stimulants were initially prescribed for 322 (64.8%) and A2A for 175 (35.2%) children. Children prescribed stimulants were more likely to have no coexisting conditions than those prescribed A2A (22.3% vs. 7.4%; p < 0.001). Coexisting ASD and sleep disorder were associated with increased likelihood of starting A2As versus stimulants (p < 0.0005; p = 0.002). The association between medication treatment and improvement varied by number of coexisting conditions for 0, 1, 2, or ≥3, respectively (84.7%, 73.8%, 72.9%, 64.6%; p = 0.031). Children with ≥3 coexisting conditions were less likely to respond to stimulants than children with no coexisting conditions (67.4% vs. 79.9%; p = 0.037).

Conclusions:

Among preschool-age children with ADHD, those with ≥3 coexisting conditions were less likely to respond to stimulants than those with no coexisting conditions. This was not found for A2A, but further research is needed as very few children with no coexisting conditions were treated with A2A.

Introduction

There are 6.1 million children diagnosed with attention-deficit/hyperactivity disorder (ADHD) in the United States, and 64% have at least one coexisting condition, which may complicate ADHD diagnosis and treatment (Danielson et al. 2018). The prevalence of ADHD in preschool-age children is reported as 2.4%, based on a recent U.S. population-based study (Danielson et al. 2018). Approximately 74% of 2- to 6-year-olds with ADHD have a diagnosis of a coexisting condition (Wilens et al. 2002).

Preschool-age children with ADHD experience difficulties in many functional domains, and may continue to experience difficulties or behavioral problems at school, at home, or with friends later on, in childhood (Wilens et al. 2002; Posner et al. 2007; Erskine et al. 2016; Fleming et al. 2017; Ros and Graziano 2018). In addition, having ADHD and one or more coexisting conditions may further impact functional impairment (Posner et al. 2007). It is important to address ADHD early on in life to help prevent future negative outcomes (Erskine et al. 2016; Harpin et al. 2016; Faraone et al. 2021).

Clinical practice guidelines recommend behavioral therapy as the first-line treatment for ADHD in preschool-age children, followed by consideration of methylphenidate, a stimulant medication, if there has not been substantial improvement and there is still moderate-to-severe functional impairment (Wolraich et al. 2019; Barbaresi et al. 2020). Between 33% and 75% of preschool-age children with ADHD receive pharmacologic treatment, and those with coexisting conditions are more likely to be prescribed medications (Pliszka and AACAP Work Group on Quality Issues 2007; Visser et al. 2016; Blum et al. 2018; Davis et al. 2020; Harstad et al. 2021).

Although methylphenidate is recommended by practice guidelines (Wolraich et al. 2019), recent studies suggest that clinicians also commonly prescribe alpha-2 adrenergic agonists (A2As) to treat ADHD in preschool children. The Society for Developmental & Behavioral Pediatrics (SDBP) Complex ADHD Guidelines suggest clinicians consider A2A in children with severe impulsivity, aggression, oppositional behavior, irritability, or moodiness, while acknowledging very limited research to support this recommendation (Barbaresi et al. 2014; Cortese et al. 2018). There are limited data on A2A use in preschoolers; however, findings from a study utilizing Medicaid claims data in Kentucky found that for preschool-age children with ADHD A2A monotherapy increased between 2012 and 2017 from 10% to 23%, with higher rates of A2A use among the youngest ages (Davis et al. 2020).

The most rigorous assessment of stimulant medication for ADHD in young children was the Preschool ADHD Treatment Study (PATS), a six-site randomized clinical trial of methylphenidate in 3- to 5.5-year-old children with ADHD (Greenhill et al. 2006; Wigal et al. 2006; Ghuman et al. 2007). This study found that methylphenidate often improved ADHD symptoms in preschool-age children, but among children with three or more coexisting conditions, there was no change in ADHD symptoms (Ghuman et al. 2007).

Previous studies have found that children with coexisting conditions are more likely to be treated with A2A, whereas those with no coexisting conditions are more likely to be treated with stimulants (Blum et al. 2018; Davis et al. 2020). However, it has not been clear if these were the initial medications chosen by clinicians, or if A2A were selected because the child did not respond well to initial treatment with a stimulant (Blum et al. 2018; Davis et al. 2020).

Therefore, the purpose of this study was to (1) determine whether the type and number of coexisting conditions are associated with the initial medication choice of stimulants or A2A for treatment of ADHD in preschool-age children, and (2) examine whether the type and number of coexisting conditions are associated with the likelihood of improvement and/or dose of medication prescribed.

Methods

Study design and setting

This was a retrospective manual electronic health record (EHR) review conducted by the Developmental Behavioral Pediatrics Research Network (DBPNet) (Blum and DBPNet Steering Committee 2012) at seven academic medical centers across the United States. The seven sites had no institutionally based, or DBPNet-specific, clinical practice guidelines for preschool ADHD during the period of data collection. Clinicians at the sites were likely familiar with the PATS and the recommendation for methylphenidate for preschool ADHD (Greenhill et al. 2006).

Participants

Records were included in the study if children had (1) an ADHD diagnosis (ICD10 codes F90.0-F90.9); (2) a prescription from a developmental-behavioral pediatrician (DBP) for a stimulant or A2A medication as a monotherapy for treatment of ADHD when the child was <72 months of age; and (3) treatment between January 1, 2013 and July 1, 2017 (final date of medication follow-up was February 27, 2019). If a child had initiated treatment before January 1, 2013, but was treated during the study time frame, visits before January 1 were also included in the data abstraction.

Children were excluded from the study if they had (1) a diagnosis of moderate or severe global developmental delay or intellectual disability and/or documentation of an overall developmental or intelligence quotient <55; or (2) psychotropic medication use (previous or current stimulant, A2A, selective serotonin reuptake inhibitor [SSRI], antipsychotic, or mood stabilizer) at the time of, or before, the initial visit to a DBP; or (3) A2A prescribed only for sleep. The Children's Hospital of Philadelphia Institutional Review Board (IRB) approved the study, and the other study sites utilized reliance agreements.

Data abstraction protocol

Study sites conducted an iterative process to create the data abstraction form and guide, which was modeled after previous studies (Barbaresi et al. 2006; Blum et al. 2018). Data abstractors were trained before initiating clinical EHR reviews and achieved >85% consistency with “gold standard” training case answers (Harstad et al. 2021). Two reviewers coded 16% of records, and the mean inter-rater agreement was 98% for all variables collected. For the rating of improved versus not improved on medication, the kappa statistic for inter-rater reliability was 0.96.

Demographic variables

Demographic variables abstracted from the EHR included age at initiation of ADHD medication, child sex, race (White, Black, American Indian, Asian, Pacific Islander, mixed, other), ethnicity (non-Hispanic, Hispanic, unknown), and insurance type (public, private, other), as well as the site and code for the prescribing clinician. Race and ethnicity were based on categories entered into the medical records by administrative staff or clinicians, and were abstracted to determine whether there were associations with the first medication prescribed and to assess the degree to which the sample reflect the diversity of the U.S. population.

Attention-deficit/hyperactivity disorder

Documentation of a clinical ADHD diagnosis (ICD10 codes F90.0-F90.9) included an inclusion criterion, as noted above. The ADHD diagnosis was based on developmental-behavioral and medical clinical history. The clinical practices at each site included the collection of parent and (if applicable) teacher rating scales, but these were not required for inclusion in the study.

Coexisting conditions

Abstracters reviewing the electronic medical record were asked to note the presence or absence of the following potentially coexisting neurodevelopmental and behavioral conditions diagnosed by the DBP at the time of the initial ADHD diagnosis: anxiety disorder, autism spectrum disorder (ASD), disruptive behavior disorder, language disorder, mild global developmental delay or mild intellectual disability, mood disorder, motor disorder including developmental coordination disorder, hypotonia, and cerebral palsy, sleep disorder, social communication disorder, and tic disorder. The number of coexisting conditions was the sum of any of the above conditions noted to be present, and was categorized as 0, 1, 2, and ≥3 coexisting conditions.

Outcomes

Improvement on medication

Improvement on medication was rated for each treatment episode, which was defined as the period of time that a child was prescribed a specific medication at a specific dose and a specific frequency (Harstad et al. 2021). The data abstractor inferred the level of improvement in ADHD symptoms based on clinic notes, which included parent reports and clinician impressions. The abstractors used precise instructions in the data abstraction guide about how to code specific phrases, consistent with the methodology previously described in detail (Harstad et al. 2021).

The Clinical Global Improvement Scale was used as a guide in judging improvement (Guy 1976). If the abstractor judged the treatment to be 1 = very much improved or 2 = much improved, the medication was coded as associated with improvement. If the abstractor judged the treatment as 3 = minimally improved or worse or could not make a determination about whether the child improved on the medication, the treatment episode was coded as not associated with improvement. Adverse effects (AEs) were not considered in judging improvement in ADHD symptoms.

To determine whether treatment with the first medication prescribed was associated with improvement, we evaluated all treatment episodes in which the child was prescribed a specific type of medication (methylphenidate-based, amphetamine-based, guanfacine or clonidine) regardless of dose, frequency, or formulation up until the first medication type prescribed was stopped, a new type of medication was added, or the child had their first visit after turning 6 years of age. As in previous analyses from this study, we considered the treatment as associated with improvement if the child was rated as improved on any treatment episode during this time frame, which we defined as a “treatment interval” (Harstad et al. 2021).

Adverse effects

AEs that occurred during medication treatment were abstracted for each preschool-age child. The data abstraction form listed common AEs: moodiness/irritability (included emotionality, excessive crying), appetite suppression, disruptive behavior (included aggression), difficulty with sleep, daytime sleepiness, stomachaches, skin picking or other repetitive behaviors, headaches, withdrawn behavior, weight loss, dizziness, and syncope. Symptoms that were present before medication use and continued during medication use were not considered AEs. If the same AE was reported at different doses for the same preschool-age child, it contributed only once to the frequency of the AE for that medication class.

Medication dosages

The total daily dose of medication prescribed during each treatment episode was recorded for the most commonly prescribed stimulant (methylphenidate) and the most commonly prescribed A2A (guanfacine). The total daily dose for dexmethylphenidate was multiplied by 2 to create an equivalent to methylphenidate dosing. The “first improved dose” is the dose of medication in which treatment was first associated with improvement. The “maximum total daily dose” prescribed is the maximum dose prescribed over a period of time associated with improvement on the medication.

Statistical analyses

Analyses were performed with Stata 17.0, with two-sided tests of hypotheses and a p-value <0.05 as the criterion for statistical significance. Means and standard deviations were reported in descriptive analysis of continuous variables that were approximately normally distributed, while medians and interquartile ranges (IQRs, 25th to 75th percentiles) were reported for continuous variables that deviated from normality. Categorical variables were tabulated. The Kappa statistic was calculated to examine the inter-rater agreement for improved versus not improved.

First, the Wilcoxon rank-sum test and the chi-square test were used to compare age and categorical variables between medication classes. Second, the proportion of the type of coexisting conditions by medication was compared in an unadjusted analysis using the chi-square test. Third, the number of coexisting conditions by the likelihood of improvement for initial ADHD treatment was compared in an unadjusted analysis using the chi-square test. This was further examined in an adjusted analysis that accounted for clustering within site and clinician, by fitting logistic models in a survey sampling framework, with stratification by clinical site and clinician as the primary sampling unit, using the approach recommended by LaVange et al. (2001).

Fourth, the proportion of children with a particular coexisting condition versus children with no coexisting condition by likelihood of improvement for initial treatment was compared using the chi-square test. Fifth, the dose of methylphenidate and guanfacine in the first treatment episode that was rated as improved was compared between children with a coexisting condition versus children with no coexisting conditions using the two-sample t-test with unequal variances.

Results

Demographics

The 497 children included in the study had a median (IQR) age at the time of ADHD medication initiation of 62 (54–67) months, were predominantly male, and were racially and ethnically diverse (Table 1). There were no significant differences by sex, race, or ethnicity in whether children were prescribed stimulants or A2A. Eighty-five (17.1%) children were reported to have no coexisting conditions; 183 (36.8%) children had one coexisting condition; 133 (26.8%) children had 2 coexisting conditions; and 96 (19.3%) children had ≥3 coexisting conditions. Having a higher number of coexisting conditions was associated with an increased likelihood that a child would be prescribed A2A versus stimulants (Table 1).

Table 1.

Demographics of Total Sample and Medication Type

Demographic characteristics	Total sample (N = 497)	Stimulant medication (N = 322)	α-2 Adrenergic agonist medication (N = 175)	Stimulant vs. α-2 adrenergic agonist medication
Demographic characteristics	n (%) or Median (IQR)	n (%) or Median (IQR)	n (%) or Median (IQR)	p
Age at ADHD medication initiation (months)	62 (54–67)	63 (58–68)	56 (49–63)	<0.001
Sex
Male	409 (82.3%)	262 (81.4%)	147 (84.0%)	0.46
Insurance type
Medicaid	276 (55.5%)	178 (55.3%)	98 (56.0%)	0.85
Race
White	299 (60.2%)	189 (58.7%)	110 (62.9%)	0.63
Black	94 (18.9%)	60 (18.6%)	34 (19.4%)
American Indian	4 (0.8%)	3 (0.9%)	1 (0.6%)
Asian	12 (2.4%)	9 (2.8%)	3 (1.7%)
Pacific Islander	1 (0.2%)	1 (0.3%)	0 (0%)
Mixed	7 (1.4%)	3 (0.9%)	4 (2.3%)
Other	46 (9.3%)	31 (9.6%)	15 (8.6%)
Unknown	34 (6.8%)	26 (8.0%)	8 (4.6%)
Ethnicity^a
Non-Hispanic	392 (85.6%)	247 (84.3%)	145 (87.9%)	0.30
Hispanic	66 (14.4%)	46 (16%)	20 (12%)	0.30
Number of coexisting conditions
0	85 (17.1%)	72 (22.4%)	13 (7.4%)	<0.001
1	183 (36.8%)	128 (39.8%)	55 (31.4%)
2	133 (26.8%)	73 (22.7%)	60 (34.3%)
≥3	96 (19.3%)	49 (15.2%)	47 (26.9%)

Chi-square analyses were conducted to examine differences between stimulants and α-2 adrenergic agonist medications.

N = 458 with known ethnicity.

ADHD, attention-deficit/hyperactivity disorder; IQR, interquartile range.

Type and number of coexisting conditions and association with medication choice

Stimulants were the initial medication prescribed for 322 (64.8%) preschool-age children and A2A for 175 (35.2%) children. As shown in Table 2, the children prescribed stimulants were more likely to have no coexisting conditions than the children prescribed A2A (22.4% vs. 7.4%; p < 0.001). Those with coexisting sleep disorders or ASD were significantly more likely to be prescribed A2A (Table 2). As we have previously shown, there were site and clinician factors that were associated with the medication prescribed. We repeated the above analyses adjusting for clustering by clinician and site, but this did not change the statistically significant results (analysis not shown).

Table 2.

Association of Common Coexisting Conditions with Clinician Medication Choice

Presence of coexisting conditions	Total sample (N = 497)	Stimulant medication (N = 322)	α-2 Adrenergic agonist medication (N = 175)	Stimulant vs. α-2 adrenergic agonist medication
Presence of coexisting conditions	n (%)	n (%)	n (%)	p
None	85 (17.1)	72 (22.4)	13 (7.4)	<0.001
Language disorder	199 (40.0)	124 (38.5)	75 (42.9)	0.35
Sleep disorder	139 (28.0)	75 (23.3)	64 (36.6)	0.002
Disruptive behavior disorder	113 (22.7)	65 (20.2)	48 (27.4)	0.066
Autism spectrum disorder	108 (21.7)	51 (15.8)	57 (32.6)	<0.001
Motor disorder^a	99 (19.9)	57 (17.7)	42 (24.0)	0.093
Mild GDD or ID^b	60 (12.1)	38 (11.8)	22 (12.6)	0.80
Anxiety disorder	24 (4.8)	16 (5.0)	8 (4.6)	0.84

Less than 2% of children with ADHD had a coexisting mood disorder, tic disorder, social communication disorder, and thus were not included in the table; chi-square analyses were conducted to examine differences between stimulants and α-2 adrenergic agonist medications.

Motor disorder includes developmental coordination disorder, hypotonia, and cerebral palsy.

Mild global developmental delay or intellectual disability.

ADHD, attention-deficit/hyperactivity disorder.

Type and number of coexisting conditions and association with likelihood of improvement

For the total sample, children with more coexisting conditions were less likely to respond to pharmacologic treatment (Table 3). Children with ≥3 coexisting conditions were less likely to respond to pharmacologic treatment than the rest of the sample in both unadjusted (64.6% vs. 75.8%; p = 0.025) and adjusted analyses (p = 0.014). The relationship between number of coexisting conditions and response to stimulants was similar to the results for the total sample, although it was not statistically significant (Table 3). Children with ≥3 coexisting conditions tended to respond to stimulants less frequently than the rest of the sample (67.4% vs. 79.9%; p = 0.052 in the unadjusted analysis), which was statistically significant in the adjusted analysis (p = 0.037). Number of coexisting conditions did not seem to impact response to A2A, but only 13 children with no coexisting conditions were treated with A2A.

Table 3.

Relationship Between Number of Coexisting Conditions and Likelihood of Improvement

No. of coexisting conditions	Total (N = 497)					Stimulant medication (N = 321)					α-2 Adrenergic agonist medication (N = 175)
	No. of improved/treated (%)	Unadjusted		Adjusted^a		No. of improved/treated (%)	Unadjusted		Adjusted		No. of improved/treated (%)	Unadjusted		Adjusted
	No. of improved/treated (%)	χ² (df)	p	χ² (df)	p	No. of improved/treated (%)	χ² (df)	p	χ² (df)	p	No. of improved/treated (%)	χ² (df)	p	χ² (df)	p
0	72/85 (84.7)	9.45 (3)	0.024	2.72 (3)	0.031	62/72 (86.1)	6.06 (3)	0.109	2.44	0.088	10/13 (76.9)	1.3 (3)	0.72	1.35 (3)	0.464
1	135/183 (73.8)					100/128 (78.1)					35/55 (63.6)
2	97/133 (72.9)					56/73 (76.7)					41/60 (68.3)
≥3	62/96 (64.6)					33/49 (67.4)					29/47 (61.7)

One child who was treated with stimulant medication (i.e., methylphenidate) did not have clinician number available and was excluded from these results, as analyses were adjusted for clustering by clinician and site.

For every coexisting condition evaluated across both classes of medications, there was a greater likelihood of improvement for preschool-age children with no coexisting conditions, compared with those with any specific coexisting conditions (Table 4), although in most cases the comparisons for individual coexisting conditions were not statistically significant. Individual conditions that were associated with statistically significant differences were ASD and anxiety disorder. When analyses were corrected for multiple comparisons, only anxiety remained significant. For these two conditions, treatment with stimulants was statistically less likely to be associated with improvement than for children with no coexisting conditions.

Table 4.

Relationship Between Type of Coexisting Condition and Likelihood of Improvement

Coexisting condition	Stimulant medication			Alpha-2 adrenergic agonist medication
Coexisting condition	No. of improved/treated (%)	χ² (df)	p, Specific coexisting condition vs. none	No. of improved/treated (%)	χ² (df)	p, Specific coexisting condition vs. none
None^a	62/72 (86.1)	Ref.	Ref.	10/13 (76.9%)	Ref.	Ref.
Language disorder	94/124 (75.8)	2.98 (1)	0.084	52/75 (69.3)	0.31 (1)	0.58
Sleep disorder	56/75 (74.7)	3.04 (1)	0.081	43/64 (67.2)	0.48 (1)	0.49
Disruptive behavior disorder	50/65 (76.9)	1.93 (1)	0.16	31/48 (64.6)	0.71 (1)	0.40
Autism spectrum disorder	35/51 (68.6)	5.47 (1)	0.019	37/57 (64.9)	0.69 (1)	0.41
Motor disorder^b	43/57 (75.4)	2.39 (1)	0.12	28/42 (66.7)	0.489 (1)	0.48
Mild GDD or ID^c	28/38 (73.7)	2.58 (1)	0.11	11/22 (50)	2.47 (1)	0.12
Anxiety disorder	9/16 (56.3)	7.49 (1)	0.006^d	4/8 (50)	1.62 (1)	0.20

Less than 2% of children with ADHD had a coexisting mood disorder, tic disorder, social communication disorder, and thus were not included in the table.

None is compared with each coexisting condition.

Motor disorder includes developmental coordination disorder.

Mild global developmental delay or intellectual disability.

Due to a Bonferroni correction, p-values <0.007 are significant.

ADHD, attention-deficit/hyperactivity disorder.

Number of coexisting conditions and association with AEs

Common AEs that occurred during medication treatment are presented in Table 5. The most common AE for preschool-age children on stimulants was moodiness/irritability. There were no significant differences in the likelihood of experiencing moodiness/irritability or other common AEs among children on stimulants with 0, 1, 2, or ≥3 coexisting conditions. The most common AE for preschool-age children on A2A was daytime sleepiness. Similarly, there were no significant differences in the likelihood of experiencing daytime sleepiness or other common AEs among children on A2A with 0, 1, 2, or ≥3 coexisting conditions.

Table 5.

Common Adverse Effects by Number of Coexisting Conditions

Adverse effects	Stimulant medication					α-2 Adrenergic agonists medication
	No. of coexisting conditions				p	No. of coexisting conditions				p
	0 (N = 72), %	1 (N = 128), %	2 (N = 73), %	≥3 (N = 49), %	p	0 (N = 13), %	1 (N = 55), %	2 (N = 60), %	≥3 (N = 47), %	p
Moodiness/irritability	54.2	48.4	46.6	53.1	0.77	30.8	36.4	25.0	23.4	0.45
Disruptive behavior	19.4	23.4	19.2	28.6	0.58	38.5	30.9	21.7	29.8	0.53
Appetite suppression	38.9	34.4	34.2	28.6	0.71	23.1	5.4	3.3	6.4	0.07
Difficulty with sleep	27.8	20.3	15.1	20.4	0.31	15.4	18.2	6.7	6.4	0.15
Daytime sleepiness	2.8	2.3	2.7	4.1	0.94	38.5	36.4	35.0	42.6	0.87
Stomachaches	8.3	18.0	8.2	14.3	0.13	7.7	9.1	1.7	2.1	0.20
Skin picking or other repetitive behavior	16.7	10.2	8.2	10.2	0.39	0	5.5	6.7	2.1	0.58

Methylphenidate and guanfacine: dose and association with improvement

Table 6 presents the first improved dose and maximum dose of each medication prescribed for children with coexisting condition for the most commonly prescribed stimulant (methylphenidate or dexmethylphenidate) and the most commonly prescribed A2A (guanfacine). In comparison with children with no coexisting conditions, there were no differences in first improved dose on methylphenidate for children with any coexisting condition. The maximum dose prescribed was lower for children with every coexisting condition, although the difference was only statistically significant for children with motor disorders.

Table 6.

Relationship of Coexisting Conditions and Medication Dose

Coexisting condition	Methylphenidate						Guanfacine
	First improved dose	t	p	Maximum dose	t	p	First improved dose	T	p	Maximum dose	t	p
	Mean (SD)	t	p	Mean (SD)	t	p	Mean (SD)	T	p	Mean (SD)	t	p
None^a	9.6 (5.1)	Ref.	Ref.	20.9 (12.4)		Ref.	0.79 (0.25)	Ref.	Ref.	1.9 (1.1)	Ref.	Ref.
Language disorder	9.9 (5.7)	0.30	0.763	17.5 (9.3)	−1.93	0.353	0.92 (0.53)	1.23	0.234	1.4 (0.75)	−1.33	0.221
Sleep disorder	10.5 (5.9)	0.83	0.41	17.7 (10.0)	−0.72	0.473	0.80 (0.42)	0.13	0.902	1.1 (0.59)	−1.98	0.084
Disruptive behavior disorder	10.9 (6.4)	1.09	0.281	20.0 (11.8)	0.30	0.763	1.1 (0.44)	2.81	0.011^b	1.5 (.54)	−1.09	0.306
Autism spectrum disorder	8.5 (5.7)	−0.895	0.375	15.3 (10.7)	−1.59	0.116	0.86 (0.59)	0.57	0.575	1.2 (0.81)	−1.68	0.128
Motor disorder	8.6 (5.2)	−0.94	0.348	15.0 (8.5)	−2.04	0.044^b	0.70 (0.41)	−0.64	0.526	0.96 (0.62)	−2.28	0.05
Mild GDD or ID^c	9.0 (5.4)	−0.46	0.645	16.4 (10.5)	−1.07	0.288	0.90 (0.18)	0.61	0.555	1.4 (0.86)	−1.17	0.262
Anxiety disorder	9.9 (5.1)	0.16	0.875	15.6 (7.7)	−1.22	0.241	0.70 (0.36)	−0.41	0.701	0.70 (0.36)	−2.82	0.02^b

Dose is in milligrams (mg).

Each coexisting condition is compared with none.

p < 0.05.

Mild global developmental delay or intellectual disability.

SD, standard deviation.

On guanfacine, the first improved dose was significantly higher for children with disruptive behavior disorders compared with no coexisting conditions (1.1 ± 0.44 mg vs. 0.79 ± 0.25 mg; p = 0.011), although there was no difference in the maximum dose prescribed. Similar to stimulants, the maximum dose of guanfacine prescribed for children with every coexisting condition evaluated was lower than that for children with none, although the only statistically significant difference was observed for anxiety disorders.

Discussion

Coexisting conditions were associated with clinicians' choices of initial medication prescribed for preschool-age children with ADHD. Those with more coexisting conditions and those with ASD or sleep disorders were more likely to be prescribed A2A. Increasing number of coexisting conditions in general, and ≥3 coexisting conditions in particular, decreased the likelihood that treatment with stimulant medication would be associated with improvement.

Although A2A were more likely to be prescribed to children with ASD or sleep disorders and stimulants were associated with a lower likelihood of improvement with an increasing number of coexisting conditions, there were not any specific coexisting conditions or any number of coexisting conditions for which treatment with A2A was associated with a higher response rate than stimulants. The finding that A2A were more likely to be prescribed to children with ASD or children with sleep disorders is consistent with previous studies, and extends those findings by demonstrating that A2A are more likely to be chosen as the initial treatment, as opposed to being used sequentially after a failed trial of stimulants (Harstad et al. 2016, 2021; Davis et al. 2020; Mittal et al. 2020).

The association of coexisting conditions with response to stimulant medication has been evaluated in the PATS (Greenhill et al. 2006; Wigal et al. 2006; Ghuman et al. 2007; Posner et al. 2007). Similar to this study, the PATS found that children with ≥3 coexisting conditions were less likely to respond to stimulants (e.g., methylphenidate in PATS) (Ghuman et al. 2007). However, the PATS excluded children with coexisting developmental disorders such as ASD and global developmental delay who are often treated for ADHD in the preschool-age range (Ghuman et al. 2007).

Given changes in the diagnostic criteria for ASD in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR™) DSM-5 (published after the PATS), we cannot rule out that some children in the PATS would have met current criteria for ASD. Nonetheless, the PATS did not include ASD in the coexisting conditions evaluated (American Psychological Association, 2022). Thus, this study extends the PATS finding of ≥3 coexisting conditions being associated with lower response rate to stimulants (Ghuman et al. 2007) to children with common developmental disorders not included in the PATS analysis. Therefore, there are a broad range of neurodevelopmental and/or psychiatric coexisting conditions that are associated with medication response and may impact treatment of ADHD in young children.

Unlike the study findings for likelihood of improvement, the frequency of any coexisting condition was not associated with the likelihood of any AE. We do not know of any other previous literature where the number of coexisting conditions is associated with AEs in preschool-age children.

Examination of whether specific coexisting conditions were associated with treatment with different doses of methylphenidate or guanfacine should be viewed as preliminary as we did not adjust for multiple comparisons so as not to miss potentially important relationships between coexisting conditions and dose of medication needed. Despite this approach, few statistically significant differences in first improved dose or maximum dose were found. Although not statistically significant for any condition other than motor disorder, the maximum dose of methylphenidate prescribed was lower for children with every coexisting condition examined than for children with none.

The likelihood of this happening by chance if the presence of coexisting conditions were not associated with the maximum dose prescribed was <1%. Further, the same pattern was seen for guanfacine as the maximum dose used in children with no coexisting conditions was higher than that for all the specific coexisting conditions evaluated. The reason for this is not clear, but may relate to increased clinician concern about AEs in children with coexisting conditions or the common advice to “start low and go slow” when using psychopharmacologic agents in young children with developmental disorders (Wolraich et al. 2019).

In this study, the majority of preschool-age children treated with ADHD medications had at least one coexisting condition, and thus may be considered as having “complex” ADHD. Guidelines on the treatment of complex ADHD describe behavioral interventions as foundational, and converging evidence from multiple studies indicates that medication response is lower in children with multiple coexisting conditions supporting the need for including behavioral and educational interventions in a multimodal treatment plan (Barbaresi et al. 2020).

Limitations

There are some important limitations of this study. Given the retrospective nature of the study, evaluation for coexisting conditions and of response to medication was not standardized across sites, and the magnitude of improvement on medication was not evaluated. Similarly, given the variation and consistency of use of baseline rating scales, the baseline severity of ADHD was not able to be determined. Children were not prescribed medications based on random assignment, and factors influencing clinicians' initial choice of medication, or decisions to increase dose or stop the medication, could not be evaluated.

In particular, clinicians may have been influenced by the high rates of AEs of stimulants that we and others have previously reported (Wigal et al. 2006; Harstad et al. 2021). Adherence to the medications prescribed could not be assessed. Preschoolers with ADHD in a developmental-behavioral pediatrics setting may have a different presentation in other settings; thus future studies should be conducted in other settings to promote generalizability.

Despite these limitations, the study has some important strengths. First, we included preschool-age children with common developmental disorders who have often been excluded from randomized clinical trials (Mittal et al. 2020), but are commonly treated in clinical practice. Second, this is the first study to evaluate the association of coexisting conditions with treatment response in a large group of preschool-age children prescribed A2A. Third, the study sample was large, racially and ethnically diverse, and from seven geographic sites from various regions in the United States. Fourth, data abstraction was standardized across sites with high inter-rater agreement.

Conclusions

Preschool-age children treated with medication for ADHD often have coexisting conditions. Coexisting ASD and sleep disorder were associated with increased likelihood of being initiated on A2A rather than stimulant medication. Children with ≥3 coexisting conditions were less likely to have reported improvement associated with stimulants, compared with those with no coexisting conditions. The association of coexisting conditions with response to A2A was less prominent than that for stimulants, although this should be interpreted with caution given the lack of random assignment to medication and the low number of children with no coexisting conditions treated with A2A. These findings support the need for comparative effectiveness studies of stimulants versus A2A to better define how to choose among these medications when treating preschool-age children with ADHD.

Clinical Significance

This is the first study to evaluate the association of ADHD and coexisting conditions on treatment response in a large group of preschool-age children prescribed A2A from seven sites across the United States. Coexisting ASD and sleep disorder were associated with increased likelihood of being initiated on A2A rather than stimulant medication. Children with 3 coexisting conditions were less likely to have reported improvement associated with stimulants, compared with those with no coexisting conditions.

Footnotes

Acknowledgments

The following individuals contributed as members of the DBPNet Steering Committee, By Institution: Albert Einstein College of Medicine/Children's Hospital at Montefiore Medical Center: Ruth Stein; Baylor College of Medicine: Robert Voigt; Boston Children's Hospital, Harvard School of Medicine: Marilyn Augustyn; Cincinnati Children's Hospital Medical Center/University of Cincinnati: Susan Wiley; Hasbro Children's Hospital/Brown Medical School: Pamela High; Kansas City Developmental Behavioral Pediatrics (KC-DBP) Consortium: Cy Nadler; Lucile Packard Children's Hospital: Heidi M. Feldman; NYU Grossman School of Medicine: Alan Mendelsohn; Rainbow Babies and Children's Hospital: Nancy Roizen; University of Arkansas for Medical Sciences: Jill Fussell; University of California, Davis, Medical Investigation of Neurodevelopmental Disorders Institute: Robin Hansen.

Authors' Contributions

All authors approved the final article as submitted and agree to be accountable for all aspects of the work.

Disclosures

The authors have no competing financial interests exist.

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