Effect of Methylphenidate on Height and Weight in Korean Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: A Retrospective Chart Review

Abstract

Objective:

The purpose of this study was to investigate the effect of methylphenidate (MPH) on growth in Korean children and adolescents with attention-deficit/hyperactivity disorder (ADHD).

Methods:

The medical records of 157 subjects (mean age 8.9±2.2 years; 134 boys) with ADHD who received treatment with MPH for at least 1 year at the Department of Psychiatry at Asan Medical Center were retrospectively reviewed. Height and weight were prospectively obtained and retrospectively gathered. Height and weight were converted to age- and gender-corrected standard scores (z scores) using norms from the Korean population. Growth changes were analyzed from the starting to the end of treatment using random coefficients models with change in weight or height z score as the dependent variable.

Results:

Weight (β = −0.109, p<0.001) and height (β = −0.072, p<0.001) z scores significantly decreased during treatment. Weight z score decreased more in girls (β = −0.247, p<0.001) than in boys (β = −0.090, p<0.001). Weight z score decreased during the 1st year of medication (β = −0.327, p<0.001 for boys; β = −0.646, p<0.001 for girls), and did not change or increase after the 1st year. Height z score significantly decreased during treatment (β = −0.072, p<0.001) after controlling for the effect of age at treatment, gender, mean daily mg/kg dose, and comorbid depressive disorder. Height z score also decreased during the 1st year of medication (β = −0.089, p<0.001) but did not change after the 1st year.

Conclusions:

These results suggest that MPH could be related to weight and height deficit in Korean children and adolescents, although the effects were minor, and disappeared after the 1st year. Because of the limitations of this study such as retrospective design, selection bias, and high attrition rate, further prospective studies are needed.

Introduction

Central nervous system stimulants such as methylphenidate (MPH) are the first-line agents in the pharmacotherapy of attention-deficit/hyperactivity disorder (ADHD) (Pliszka 2007). Although 75–80% of children and adolescents with ADHD show a significant drug response (Barkley 2006), several adverse effects limit the utilization of MPH. Decreased appetite and growth deficit are particular concerns (Barkley 2006).

Long-term follow-up studies report inconsistent results on the effect of MPH on weight and height, with some studies demonstrating a small decrease in expected height gain (Poulton 2005; Faraone and Giefer 2007; Swanson et al. 2007) and others demonstrating no effect on adult height (Hechtman et al. 1984; Klein et al. 1988). The Multimodal Treatment Study of ADHD 3-year follow-up showed that the group treated with stimulants had an average of 2.0 cm less height gain and 2.7 kg less weight gain than the unmedicated group (Swanson et al. 2007), although the clinical significance of these effects is debated (Spencer et al. 2006). Spencer et al. (1996) reported that growth delay in children and adolescents with ADHD was more related to ADHD itself than to MPH treatment, and Biederman et al. (2010) reported that neither ADHD nor MPH treatment influenced adult height at 10 year follow-up. In a recent review, Faraone et al. (2008) concluded that treatment with stimulants early in childhood modestly reduced expected height and weight, but that these effects attenuated over time, and that ultimate adult growth parameters were not affected. However, most studies have been conducted in Western countries, and only one study examined the effect of MPH on growth in an Asian population (Zhang et al. 2010). Side effects of stimulant as well as response to stimulant drugs are known to be modulated by ethnicity (Hart et al. 2012). Therefore, the aim of this study was to investigate the effect of MPH on growth in Korean children and adolescents with ADHD.

Methods

We retrospectively reviewed the medical records of 157 children and adolescents with ADHD who were prescribed MPH from March 2004 to February 2011 at the Department of Psychiatry at Asan Medical Center. All subjects had to meet the following inclusion criteria: 1) Being between 5 and 14 years of age at the start of treatment; 2) being diagnosed with ADHD according to the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (American Psychiatric Association 1994); 3) receiving treatment with MPH for at least 1 year; and 4) having a baseline weight and height z score>−2.0 relative to the general Korean population. Subjects were excluded from the study if they had one or more of the following exclusion criteria: 1) Prior exposure to a central nervous system stimulant or atomoxetine; 2) having initiated MPH treatment before the age of 5 years; 3) intelligent quotient <70 on the Korean Educational Developmental Institute's Wechsler Intelligence Scale for Children (Park et al. 2002); 4) past and/or current history of developmental disorder, including autism spectrum disorder; 5) past and/or current history of schizophrenia, bipolar disorder, or other psychosis; 6) current seizure disorder; 7) mean compliance for the whole treatment period <80%; 8) taking an adjunct medication that could affect growth; and 9) past and/or current medical illness that could induce growth suppression.

All subjects underwent general clinical diagnostic procedures. A child psychiatrist monitored treatment, and measurements of height and weight were taken at every visit. Visits occurred at least every 3 months. Height and weight were, therefore, prospectively obtained and retrospectively gathered. Height and weight were converted to age- and gender-corrected standard scores (z scores) using norms from a “2007 Korean child and adolescent physical development standard value” (Korea Center for Disease Control and Prevention 2007). A z score of 0 indicates the measurement is at or near the mean of the population, whereas a z score of +1 or −1 indicates a measurement of one standard deviation more or less than the mean, respectively. The z score statistic allows evaluation of variations compared with the population mean over time, and can be useful for assessment of longitudinal outcomes such as weight and height. Medication type (osmotic-release oral system [OROS], extended release [ER], or immediate release [IR]), duration, and daily mg/kg dose were also gathered retrospectively from patient medical records. Because the study was framed retrospectively using medical records, there were missing data at various time points.

We analyzed growth from the start to the end of treatment using a random coefficients model with change in weight or height z score from baseline (Δ weight and Δ height z score, respectively) as the dependent variable, and the following independent variables: Baseline weight or height z score, gender, age at first treatment, medication type (OROS, ER, or IR), medication duration, mean daily mg/kg dose, and comorbid diagnoses. The interaction between medication duration and each other variable was evaluated in this univariate model. Age at first treatment, gender, mean daily mg/kg dose, and independent variables that were significant in the univariate model were included in a multivariate model. To examine whether the slopes of Δ weight and Δ height z scores differed across the 1st, 2nd, and beyond the 2nd year of medication, the model evaluated the interaction between medication duration and time period (year 1, year 2, and beyond year 2) adjusting for the age at first treatment, gender, mean daily mg/kg dose, and independent variables that were significant in the univariate model.

Statistical analyses were performed using SAS (version 9.2, SAS, Cary, NC) and statistical significance was defined for all other comparisons at p value of <0.05. All comparisons were two tailed.

Results

Demographic characteristics

Of the 157 subjects, 134 (85.4%) were male and 23 (14.6%) were female. The mean age at first treatment was 8.9±2.2 years (range, 5.7–13.8 years). One hundred and twelve subjects (71.3%) had combined type ADHD, 44 (28.0%) had inattentive type, and 1 (0.6%) had hyperactive-impulsive type. Oppositional defiant disorder (ODD) was the most common comorbid diagnosis (n=48, 30.6%), followed by tic (n=28, 17.8%), anxiety (n=18, 11.5%), depressive (n=7, 4.5%), and elimination disorder (n=4, 2.5%). Mean full-scale intelligent quotient was 104.5±15.3 (range, 71–143).

Forty-one subjects (26.1%) were treated with MPH ER, 82 (52.2%) with MPH OROS, and 34 (21.7%) with a combination of two MPHs or by switching from one MPH to another. The mean daily dose of MPH was 35.0±12.4 mg (range, 10.0–70.5 mg), and the mean daily mg/kg dose was 0.98±0.27 mg/kg (range, 0.23–1.73 mg/kg). The mean height and weight z scores at baseline were 0.38±0.99 (range, −1.88–2.78) and 0.50±0.98 (range, −1.84–2.94), respectively.

The mean duration of follow-up was 28.8±16.1 months (range, 12–88 months). Seventy-four subjects were followed up >2 years, and 83 subjects were followed up between 1 and 2 years. Age at first treatment, baseline weight, and height z score were not different between the two groups (p=0.177, p=0.198, p=0.071, respectively), but boys were more likely to be followed up >2 years than were girls (p=0.008). Δ weight and Δ height z score for the 1st year of treatment were not different between the two groups (p=0.300, p=0.348, respectively). Mean daily mg/kg dose was 1.00±0.26 mg/kg at the 2nd year (n=74) and 1.00±0.25 mg/kg at the 3rd year (n=46).

Effect of MPH on weight

Weight z score significantly decreased during treatment (β = −0.109, p<0.001). In an 8-year-old boy with a weight z score of 0, that is, at the 50th percentile, at the start of MPH treatment, weight would be 0.67 kg less than expected after 1 year of treatment.

In the univariate random coefficients model, baseline weight z score (p=0.184), age at first treatment (p=0.167), medication type (p=0.115 for MPH ER, p=0.856 for MPH OROS, vs. MPH IR), mean daily mg/kg MPH dose (p=0.577), comorbid diagnosis of ODD (p=0.265), anxiety (p=0.533), depression (p=0.520), tic (p=0.055), or elimination disorder (p=0.937) were not associated with Δ weight z score, but gender was significantly associated with Δ weight z score (p=0.002). In the multivariate random coefficients model (Table 1), there was significant interaction between gender and medication duration (p=0.003). Weight z score decreased more in girls (β = −0.247, p<0.001) than in boys (β = −0.090, p<0.001).

Table 1.

Results of the Multivariate Random Coefficients Model for the Change in Weight Z Score from the Start of Treatment (Δ Weight Z Score)

		β	SE	p value	p value ^a
Age at first treatment		−0.015	0.010	0.147
Gender	Boys	0.055	0.063	0.387
	Girls	(reference)
Mean daily mg/kg dose		−0.076	0.083	0.360
Medication duration^b	Boys	−0.090	0.018	<0.001	0.003
	Girls	−0.247	0.050	<0.001

The model included age at first treatment, gender, daily mg/kg dose, medication duration, and the interaction terms (medication duration×gender).

Comparison of the slope of Δ weight z score to the slope in girls (medication duration×gender).

Slope of Δ weight z score per year.

In a model to examine whether the slopes of Δ weight z score differed across the 1st, 2nd, and beyond the 2nd year of medication (Table 2), there were significant interactions between medication duration and gender (p=0.027), between medication duration and time period (p<0.001), and among medication duration, gender, and time period (p<0.001). Weight z score decreased during the 1st year of medication (β = −0.327, p<0.001 for boys; β = −0.646, p<0.001 for girls), did not change during the 2nd year of medication (β=0.004, p=0.926 for boys; β = −0.115, p=0.076 for girls), and increased after the 2nd year of medication for boys (β=0.068, p=0.008), but did not change after the 2nd year for girls (β=0.120, p=0.066).

Table 2.

Results of the Multivariate Random Coefficients Model for the Change in Weight Z Score from the Start of Treatment According to Time Period (Δ Weight Z Score)

		β	SE	p value
Age at first treatment		−0.012	0.010	0.226
Gender	Boys	0.020	0.065	0.758
	Girls	(reference)
Mean daily mg/kg dose		−0.047	0.081	0.557
Medication duration of boys^a	First year	−0.327	0.033	<0.001
	Second year	0.004	0.042	0.926
	After the second year	0.068	0.026	0.008
Medication duration of girls^a	First year	−0.646	0.075	<0.001
	Second year	−0.115	0.065	0.076
	After the second year	0.120	0.065	0.066

The model included age at first treatment, gender, daily mg/kg dose, medication duration, time period, and the interaction terms (medication duration×gender, medication duration×time period, and medication duration×gender×time period).

The three interaction terms were significant (medication duration×gender p=0.027, medication duration×time period p<0.001, medication duration×gender×time period p<0.001).

Slope of Δ weight z score per year.

Effect of MPH on height

Height z score significantly decreased during treatment, although the β coefficient was small (β = −0.072, p<0.001). In an 8-year-old boy with a height z score of 0 at the start of MPH treatment, height would be 0.43 cm less than expected after 1 year of treatment.

In the univariate random coefficients model, baseline height z score (p=0.351), gender (p=0.526), age of starting medication (p=0.568), medication type (p=0.321 for MPH ER, p=0.819 for MPH OROS, vs. MPH IR), mean daily mg/kg MPH dose (p=0.102), comorbid diagnosis of ODD (p=0.496), anxiety (p=0.250), tic (p=0.061), or elimination disorder (p=0.940) were not associated with Δ height z score, but comorbid depressive disorder (β=0.196, p=0.008) was significantly associated with Δ height z score. In the multivariate random coefficients model (Table 3), height z score significantly decreased during treatment (β = −0.072, p<0.001) after controlling the effect of age at treatment, gender, mean daily mg/kg dose, and comorbid depressive disorder.

Table 3.

Results of the Multivariate Random Coefficients Model for the Change in Height Z Score from the Start of Treatment (Δ Height Z Score)

		β	SE	p value
Age at first treatment		0.006	0.007	0.372
Gender	Boys	−0.015	0.043	0.726
	Girls	(reference)
Mean daily mg/kg dose		0.086	0.058	0.140
Comorbid depressive disorder		0.184	0.073	0.013
Medication duration^a		−0.072	0.015	<0.001

The model included age at first treatment, gender, daily mg/kg dose, comorbid depressive disorder, and medication duration.

Slope of Δ height z score per year.

The interaction between medication duration and time period was significant (p=0.004). Height z score decreased during the 1st year of medication (β = −0.089, p<0.001), but did not change after the 1st year (Table 4).

Table 4.

Results of the Random Coefficients Model for the Change in Height Z Score from the Start of Treatment According to Time Period (Δ Height z Score)

		β	SE	p value
Age at first treatment		0.006	0.007	0.381
Gender	Boys	−0.004	0.044	0.934
	Girls	(reference)
Mean daily mg/kg dose		0.091	0.059	0.123
Comorbid depressive disorder		0.182	0.074	0.015
Medication duration^a	First year	−0.089	0.024	<0.001
	Second year	−0.015	0.032	0.632
	After the second year	−0.005	0.021	0.802

The model included age at first treatment, gender, daily mg/kg dose, comorbid depressive disorder, time period, medication duration, and interaction between medication duration and time period.

The interaction between medication duration and time period was significant (p=0.004).

Slope of Δ height z score per year.

Discussion

The results of this study suggest that MPH treatment is related to growth deficit in Korean children and adolescents with ADHD. However, in an 8-year-old boy with a weight and height the same as the mean of the general population, the estimated increase in weight and height in the 1st year of MPH treatment would be only 0.67 kg and 0.43 cm less than the expected increase in the general population, suggesting that the effect of MPH on growth is clinically insignificant. Moreover, the effect of MPH treatment on growth was attenuated over time.

These results are consistent with previous studies that concluded that stimulant therapy may be associated with a reduction in expected height gain, and that the impact of stimulants on height and weight attenuated over time such that final adult height was not affected (Poulton 2005; Spencer et al. 2006; Faraone et al. 2008). Our results are also concurrent with the only previous study from Asia, which found that MPH could be associated with a small but significant deceleration of height velocity, and that growth inhibition is at its most significant during the 1st year of treatment (Zhang et al. 2010). It is still controversial whether MPH affects growth, as well as whether the effect of MPH on growth differs according to race/ethnicity. Further studies, especially from non-Western countries, are needed to resolve these issues.

In our study, gender modulated the effect of MPH on weight but not on height, and comorbid depressive disorder was associated with height growth. Biederman et al. (2010) found that major depression was associated with greater weight in females with ADHD and with smaller height in males with ADHD. However, in most previous studies, there has been no difference between boys and girls in the effect of MPH on growth (Biederman et al. 2003, 2010; Zhang et al. 2010) and comorbid disorders were not associated with height or weight increase (Kramer et al. 2000; Biederman et al. 2003). Whether or not the effect of MPH on growth is different according to gender or comorbid disorder should be clarified in future studies.

Several mechanisms have been proposed to explain the effect of MPH on growth. First, suppression of appetite is common among children taking MPH (Wilens et al. 2006; Medori et al. 2008; Newcorn et al. 2008), and reduced caloric intake can negatively affect potential growth in children. Pharmacological studies from Asian countries reported relatively higher rate of appetite loss (26.1–53.1%) (Gau et al. 2006; Lee et al. 2007; Kim et al. 2010) than in the studies from Western countries (2.3∼25.2%) (Graham et al. 2011). However, Asian mothers appeared to relate eating behaviors to attachment or behavior control (Geng et al. 2009), and are less likely to allow children to leave food (Hackett and Hackett 1994). Therefore, there is a possibility that Asian mothers might more sensitively notice appetite loss. Further research is needed into ethnic differences on the side effects of MPH and their possible influence on the MPH effect on growth. Second, MPH has a potent effect on the dopaminergic system, which is involved in the regulation of growth hormone (GH) secretion (Delitala et al. 1987). However, in contrast to the acute effects of MPH on GH, long-term treatment with MPH was not associated with GH response (Graham et al. 2011). Third, stimulants might slow down the growth of cartilage tissue and bone turnover in children with ADHD (Poulton et al. 2012). However, in an animal study, the effects of MPH treatment on bone mineralization were ameliorated within 5 weeks (Komatsu et al. 2012). These normalizations of GH response and bone mineralization could explain why the initial effect of stimulants on growth appears to attenuate over time.

Some limitations should be considered when interpreting our findings. First, this study was a retrospective chart review. Second, only subjects who received MPH treatment for at least 1 year were included. This may have induced a selection bias, as subjects whose growth was less affected may be more likely to be treated for >1 year. A prospective longitudinal study that considers dropouts is needed to resolve this issue. Third, high attrition rate after the 2nd year, especially in girls, should be considered. Fourth, this study did not include a control group of children with unmedicated ADHD or children medicated with nonstimulants. This meant that it was not possible to determine whether differences in growth between the study population and the general population were the result of ADHD or the result of MPH treatment. There are ongoing prospective studies, such as the Attention-Deficit/Hyperactivity Disorder Drugs Use Chronic Effects (ADDUCE) study, with larger numbers and more controls, which one hopes will reveal the effects of treatment on ADHD children (http://www.adhd-adduce.org/page/view/40/Aims+of+the+ADDUCE+Project). Fifth, this study did not consider the influence of genetic factors, such as mid-parental height. Sixth, the age of the subjects ranged from 5 to 14 years. This wide age range might cause a bias in growth rates, in particular between females and males, which is known to differ as puberty occurs at different time points.

Moreover, we did not consider the effect of puberty. The impact of MPH on puberty has not yet been studied, but prolonged treatment (>3 years) with stimulant medication was associated with a slower rate of physical development during puberty in boys (Poulton et al. 2013). Therefore, future studies that evaluate Tanner stage of development are needed.

Despite these caveats, our study has following strengths: 1) Our subjects were all treatment naïve; therefore, growth measurements could be obtained prior to treatment onset; 2) we examined the effect of MPH without the confounding effect of medications or medical illnesses that can influence growth; and 3) our sample was from an Asian country.

Conclusions

This retrospective chart review suggests that MPH treatment could be related to weight and height deficit in Korean children and adolescents with ADHD after controlling the effect of age at treatment, gender, and mean daily mg/kg dose, although the effects were minor and disappeared after the 1st year. Because of the limitations of this study such as retrospective study design, selection bias, and high attrition rate, further prospective studies are needed.

Clinical Significance

Treatment with MPH is related to a small but significant weight and height deficit in Korean children and adolescents with ADHD. Gender modulated the effect of MPH on weight.

Footnotes

Disclosures

Dr. Kim is supported by the National Research Foundation of Korea (grant number 2012R1A1A3010048). The other authors have nothing to disclose.

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