Abstract
Objectives:
The current study evaluated the long-term effects of methylphenidate (MPH) discontinuation on growth parameters in Turkish children and adolescents with attention-deficit/hyperactivity disorder (ADHD).
Experimental design:
432 children and adolescents (aged 6–18 years) with ADHD receiving MPH for at least 1 year between March 2012 and January 2019 were included in a retrospective cohort study. We analyzed weight, height, and body mass index (BMI) standard deviation z scores (SDS) of groups that either did (ADHD-C) or did not (ADHD-DC) discontinue MPH. Growth parameters were converted to z scores as normative values for the Turkish population to compare the measurements at baseline and the last follow-up visit by using the paired sample t-test.
Principal observations:
In patients from the ADHD-C group, statistically significant negative correlations were found between age at starting MPH and differences in weight and height SDS between baseline and follow-up. Children had a greater reduction in weight and height compared to adolescents. When we evaluated the differences in pre-and post-treatment growth factors, we found no significant differences between the groups in terms of growth parameters.
Conclusions:
Our data showed that chronic use of MPH was likely responsible for changes in height and weight parameters.
Keywords: methylphenidate, drug holidays, discontinuation, ADHD, height, weight
Introduction
Attention-deficit/hyperactivity disorder (ADHD) is a chronic disorder characterized by age- inappropriate patterns of severe and persistent inattention, hyperactivity, and impulsivity which starts during childhood and frequently persists into adulthood.1 Stimulants (e.g., methylphenidate [MPH], amphetamines) are frequently prescribed as the first-line medication for its treatment.2 During the last decade, numerous randomized and observational studies have been focused on the efficacy and safety of ADHD medications. The most common adverse effects associated with MPH are insomnia, loss of appetite with weight loss or expected weight gain failure, mood fluctuations, and the apparition of motor and/or vocal tics, headache, and abdominal pain.3,4
The neurophysiological mechanisms underlying the loss of appetite observed due to MPH use and the associated weight loss or the discontinuation of an expected weight gain are not yet fully understood. In an attempt to explain why MPH causes weight loss, at least three theories have been proposed: metabolic changes such as decreased food intake as a result of the loss of appetite, early fat loss, and increased mobilization of lipids.5,6 In addition to the effects of MPH on appetite reduction via the central nervous system, other mechanisms such as suppression of growth hormone, an effect on growth factors of hepatic tissue, or suppression of chondrocyte cell proliferation and chondrogenic differentiation have also been suggested.7–9 Although a recent review and meta-analysis reported that the prevalence of obesity in children and adolescents with ADHD was 40% higher when compared with healthy children and adolescents, it is remarkable that one of the adverse effects of MPH is thought to be growth delay.10 Also, long-term psychostimulants treatment was an important predictor of final height, weight, and BMI (a reduction in adult height, and an increase in weight and body mass index).11
Most of the literature regarding the treatment of ADHD is based on treatment onset and the adverse effects of the drugs, but there is little commentary on the discontinuation of the drugs.12 Among treated patients, ‘drug holidays’ may or may not be planned. However, there is insufficient information about what to expect in patients who do not respond to treatment or how long the effects of treatment last after drug discontinuation. No prior work has randomly assigned children with documented growth suppression to continuous versus interrupted dosing to evaluate impacts on growth. Only one recent study has examined the effects of drug holidays, weight recovery treatments, and caloric supplementation on growth parameters.13 Therefore, physicians should give importance to the treatment modality after discontinuation of the drug and to relapse issues.14
The aim of this study was to determine the long-term effects of MPH discontinuation on growth parameters in children and adolescents with ADHD. We anticipated that (1) the long term effects of methylphenidate discontinuation would show a positive effect on growth parameters; and (2) the different treatment-related factors (sex, age at starting treatment, the dosage of MPH, and duration of treatment) to have associated with the final weight, height, and body mass index (BMI) standard z scores.
Methods
This study is a retrospective chart review of children and adolescents admitted to the outpatient unit. The data for the present study were collected between March 2012 and January 2019 from a chart review using medical records of the Department of Child and Adolescent Psychiatry at a tertiary-care university hospital. The inclusion criteria for eligibility in this study were: (1) Diagnosis of ADHD according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV); and previously treatment-naive (2) history of treatment with MPH (osmotic-release, immediate-release, and pellets) for at least one year. The exclusion criteria were: (1) a positive history or diagnosis of severe medical diseases (e.g., hepatic, gastrointestinal, or metabolic disturbances) that could affect growth parameters; (2) presence of any concomitant clinically unstable psychiatric condition; (3) those with concomitant treatment with medications other than MPH (e.g., neuroleptics, anticonvulsants, cortisol, mood stabilizers, thyroid medications); and (4) cases with a single period and a shorter drug holidays of less than 3 months.
The study sample was divided into two groups according to their history of continuation or discontinuation of treatment. The first group (ADHD-C) consisted of patients who were followed with the diagnosis of ADHD between March 2012 and January 2019 and were treated with MPH continuously for at least one year (7 days per week). The second group (ADHD-DC) was constituted by patients who were followed for ADHD between March 2012 and January 2019 and were treated with MPH for at least one year but discontinued MPH for at least 3 months during this treatment period (i.e., took ‘drug holidays’) for various reasons. In accordance with the study design; the height, weight, and BMI values of the cases in the ADHD-DC group at the end of the drug holidays were analyzed. Growth parameters were converted to z scores using normative values for the general population15 at baseline and the last follow-up visit.
All the data analyses were performed using the Statistical Package for the Social Sciences (SPSS v.22.0, IBM, New York) and statistical significance was defined for all comparisons at p-value of <0.05. Before the statistical analysis was performed, the fitness of the data to normal distribution was tested. In the interpretation of the variables, descriptive statistical techniques, and quantitative data analysis were used. The independent sample t-test was used to compare study groups. The paired sample-test was preferred to demonstrate the change in a study group before and after stimulant treatment. Pearson’s coefficients were used to evaluate the correlations among treatment characteristics and growth parameters.
To test the effect of discontinuation on growth outcomes, repeated-measures ANOVA was implemented by including z-scores for weight, height, and BMI just before and after MPH treatment. Repeated measures ANOVA models adjusted for the daily dose and the duration of stimulant medications were also used to compare children between adolescents. All results were adjusted for confounding effects of age at treatment-onset, the mean daily dose of MPH, and the duration of treatment as potential moderators. Finally, we implemented multiple regression analysis to explain the variance in final z-scores for weight, height, and BMI. The Local Ethics Committee of the university hospital approved the study.
Results
Demographic Characteristics
We identified 432 children and adolescents eligible for inclusion. Descriptive data on the study groups are presented in Table 1. The mean ages of the ADHD-C group and ADHD-DC group when they started treatment were 9.78 ± 2.74 years and 9.82 ± 2.63 years, respectively. There was no statistically significant difference between the groups in terms of the mean age (F = 0.708, p = 0.837). The two groups of children and adolescents were not different concerning sex, treatment duration, MPH dosage (mg/d) (SD), and MPH dosage [mg/(kg/d)] (SD) (Table 1).
Table 1. Results of Sociodemographic Data and Clinical Assessment.
| Variable | ADHD-C (n = 262) | ADHD-DC (n = 170) | Test statistic, p value, post hoc comparison |
|||
| Age, M (SD) | 9.78 (2.74) | 9.82 (2.63) | p = 0.837 | |||
| Age group | ||||||
| Children: 6–12 years, n (%) | 208 (79.39%) | 132 (77.65%) | p = 0.802 | |||
| Adolescents: 13–18 years, n (%) | 54 (20.61%) | 38 (22.35%) | ||||
| Sex | ||||||
| Males, n (%) | 197 (75.2%) | 132 (77.6%) | p = 0.559 | |||
| Females, n (%) | 65 (24.8%) | 38 (22.4%) | ||||
| Treatment: MPH | ||||||
| Dose (mg/d) (SD) | 25.47 (9.62) | 27.36 (10.67) | t = 1.549, p = 0.214 | |||
| Dose [mg/(kg/d)] (SD) | 1.35 (0.52) | 1.28 (0.48) | t = 2.324, p = 0.429 | |||
| Duration (months) (min-max) | 28 (12–113) | 25 (12–113) | t = 10.867, p = 0.618 | |||
| Baseline Weight SDS | 0.63 (1.27) | 0.59 (1.31) | t = 0.293, p = 0.770 | |||
| Baseline Height SDS | 0.75 (1.46) | 0.73 (1.42) | t = 0.132, p = 0.895 | |||
| Baseline BMI SDS | 0.28 (1.20) | 0.25 (1.23) | t = 0.211, p = 0.833 |
ADHD-C, attention-deficit/hyperactivity disorder-continue; ADHD-DC, attention-deficit/hyperactivity disorder-discontinue; MPH, methylphenidate, mean ± standard deviation (M ± SD), median (min-max), n (number of patients) and percentage (%).
Growth Parameters at Baseline
At baseline, before starting treatment, patients in the ADHD-C group showed weight (baseline weight SDS [SDS]: 0.63 [1.27]), height (baseline height SDS [SDS]: 0.75 [1.46]) and BMI (baseline BMI SDS [SDS]: 0.28 [1.20]). Before starting treatment, patients in the ADHD-DC group showed height (baseline height SDS [SDS]: 0.73 [1.42]), weight (baseline weight SDS [SDS]: 0.59 [1.31]) and BMI (baseline BMI SDS [SDS]: 0.25 [1.23]). The differences between groups for those parameters were not were not statistically significant (Table 1).
Growth Parameters After Treatment
A significant decrease in weight-z score from the initiation of medication was identified (baseline weight-z score [SDS]: 0.61 [1.28], follow-up: 0.20 [1.30]; p**<0.001). Height-z score significantly decreased during treatment: 0.74 [1.43] at baseline and 0.07 (4.49) at follow-up, p**< 0.001. There were significant differences in pre- and post-treatment BMI z score [SDS]: baseline 0.27 [1.21], follow-up: 0.06 (1.23), p**<0.001. However, considering whether patients were ADHD-C or ADHD-DC, there were significant differences in pre-and post-treatment weight-z score [SDS] and BMI-z score [SDS] (Table 2).
Table 2. Comparison of Height, Weight and BMI at Baseline and Follow up Data of Methylphenidate Treatment (ADHD-C and ADHD-DC).
| BASELINE (T1) | TOTAL SAMPLE (N = 432) FOLLOW-UP (T2) |
P | BASELINE (T1) | ADHD-C (N = 262) FOLLOW-UP (T2) |
P | BASELINE (T1) | ADHD-DC (N = 170) FOLLOW-UP (T2) |
P | ||||||||||
| Weight SDS | 0.61 (1.28) | 0.20 (1.30) | **<0.001 | 0.63 (1.27) | 0.23 (1.27) | **<0.001 | 0.59 (1.31) | 0.16 (1.35) | **<0.001 | |||||||||
| Height SDS | 0.74 (1.43) | 0.07 (4.49) | **<0.001 | 0.75 (1.46) | 0.29 (1.33) | **<0.001 | 0.73 (1.42) | −0.28 (1.97) | 0.057 | |||||||||
| BMI SDS | 0.27 (1.21) | 0.06 (1.23) | **<0.001 | 0.28 (1.20) | 0.08 (1.22) | **<0.001 | 0.25 (1.23) | 0.04 (1.26) | *0.002 |
ADHD-C, attention-deficit/hyperactivity disorder-continue; ADHD-DC, attention-deficit/hyperactivity disorder-discontinue; MPH, methylphenidate; BMI, body mass index; n (number of patients); SDS, standard deviation score; *p < 0.05, **p < 0.01. p values from paired t-tests.
MPH and Growth Parameters by Sex
When stratifying the analysis by sex, statistically significant differences in pre- and post-treatment weight-z score [SDS] and BMI-z score [SDS] were found. Additionally, boys in the ADHD-C group showed a statistically significant decrease in height (baseline height-z score [SDS]: 0.81 [1.46]; follow-up height-z score [SDS]: 0.33 [1.31]; p**< 0.001), while in boys in the ADHD-DC group, the height-z score was not affected by treatment (Table S1).
Table S1. Comparison of Height, Weight and BMI at Baseline and Follow up Data of Methylphenidate Treatment by Sex (ADHD-C and ADHD-DC).
| ADHD-C | ADHD-C | |||||||||||||||||||||||
| BASELINE (T1) |
GIRLS(N = 65) FOLLOW-UP (T2) |
P | BASELINE (T1) |
BOYS(N = 197) FOLLOW-UP (T2) |
P | BASELINE (T1) |
GIRLS(N = 38) FOLLOW-UP (T2) |
P | BASELINE (T1) |
BOYS(N = 132) FOLLOW-UP (T2) |
P | |||||||||||||
| Height-SDS | 0.57 (1.44) |
0.15 (1.39) |
**<0.001 | 0.81 (1.46) |
0.33 (1.31) |
**<0.001 | 0.62 (1.34) |
−0.46 (0.86) |
**<0.001 | 0.76 (1.44) |
−0.39 (7.88) |
0.094 | ||||||||||||
| Weight-SDS | 0.29 (1.19) |
−0.07 (1.28) |
**<0.001 | 0.74 (1.28) |
0.34 (1.26) |
**<0.001 | 0.08 (1.25) |
−0.37 (1.20) |
**<0.001 | 0.71 (1.31) |
0.31 (1.35) |
**<0.001 | ||||||||||||
| BMI-SDS | 0.04 (1.13) |
−0.17 (1.23) |
*<0.05 | 0.36 (1.21) |
0.15 (1.20) |
**<0.001 | −0.15 (1.14) |
−0.53 (1.13) |
*<0.05 | 0.37 (1.23) |
0.21 (1.25) |
*<0.05 | ||||||||||||
ADHD-C, attention-deficit/hyperactivity disorder-continue; ADHD-DC, attention-deficit/hyperactivity disorder-discontinue; MPH, methylphenidate; BMI, body mass index; SDS, n (number of patients); standard deviation score; *p < 0.05, **p < 0.01. p values from paired t-tests.
MPH and Growth Parameters by Age
When stratifying the analyses for age, separating children (6–12 years old at baseline) and adolescents (13–18 years old at baseline), in children in the ADHD-C group, height, weight, and BMI were slightly affected by treatment. This difference was not seen if MPH was started during adolescence except in BMI-z score. In such cases, the BMI-z score was even slightly above the average at follow-up (Table S2). In children in the ADHD-DC group, significant differences were observed in weight and BMI-z score, but not in the adolescence group.
Table S2. Comparison of Height, Weight and BMI at Baseline and Follow up Data of Methylphenidate Treatment by Age (ADHD-C and ADHD-DC).
| ADHD-C | ADHD-C | |||||||||||||||||||||||
| BASELINE (T1) |
CHILDREN(N = 208) FOLLOW-UP (T2) |
P | BASELINE (T1) |
ADOLESCENTS(N = 54) FOLLOW-UP (T2) |
P | BASELINE (T1) |
CHILDREN(N = 142) FOLLOW-UP (T2) |
P | BASELINE (T1) |
ADOLESCENTS(N = 28) FOLLOW-UP (T2) |
P | |||||||||||||
| Height-SDS | 0.91 (1.45) |
0.37 (1.34) |
**<0.001 | 0.11 (1.30) |
−0.04 (1.26) |
0.229 | 0.83 (1.38) |
−0.32 (2.60) |
0.071 | 0.23 (1.50) |
−0.07 (1.25) |
0.108 | ||||||||||||
| Weight-SDS | 0.75 (1.23) |
0.29 (1.22) |
**<0.001 | 0.16 (1.31) |
0.01 (1.44) |
0.348 | 0.65 (1.25) |
0.18 (1.30) |
**<0.001 | 0.27 (1.53) |
0.07 (1.58) |
0.351 | ||||||||||||
| BMI-SDS | 0.31 (1.21) |
0.11 (1.16) |
**<0.001 | 0.15 (1.18) |
−0.10 (1.40) |
**<0.005 | 0.26 (1.19) |
0.03 (1.22) |
*<0.05 | 0.20 (1.41) |
0.10 (1.46) |
0.676 | ||||||||||||
ADHD-C, attention-deficit/hyperactivity disorder-continue; ADHD-DC, attention-deficit/hyperactivity disorder-discontinue; MPH, methylphenidate; BMI, body mass index; SDS, n (number of patients); standard deviation score; *p < 0.05, **p < 0.01. p values from paired t-tests.
Among the children, BMI-z score significantly decreased during treatment (baseline BMI-z score [SDS]: 0.29 ± 1.19; and follow-up BMI-z score [SDS]: −0.21 ± 0.69; p < 0.001), but similar changes were not observed if MPH was started during adolescence. In such cases, BMI-z score [SDS] was even slightly above the average at follow-up (baseline BMI-z score [SDS]: 0.18 ± 1.26, follow-up BMI-z score [SDS]: −0.19 ± 0.91; p = 0.063) (Table S2).
The Effect of Discontinuation on Growth Parameters Between Baseline and Follow-Up
The possible moderator effect of discontinuation was also tested using the repeated measure ANOVA in all subjects. Table 3 demonstrates the growth parameters of patients before and after methylphenidate treatment. Additionally, in repeated measures ANOVA models adjusted for treatment dose and duration, children had a greater reduction in weight (F = 9,692, p* < 0.05) and height (F = 11,997, p** < 0.001) but not in BMI (F = 0,053, p = 0,817) compared to adolescents.
Table 3. The Effect of Discontinuation on Growth Parameters between Baseline and Follow-up Period.
| Growth parameters | ADHD-C, n = 262 | ADHD-DC, n = 170 | F* | p | ||||
| Height z scores, mean ± SD | 0.113 | 0.737** | ||||||
| Before methylphenidate | 0.75 ± 1.46 | 0.73 ± 1.42 | ||||||
| At the end of treatment | 0.29 ± 1.33 | −0.28 ± 1.97 | ||||||
| Weight z scores, mean ± SD | 0.497 | 0.481*** | ||||||
| Before methylphenidate | 0.63 ± 1.27 | 0.59 ± 1.31 | ||||||
| At the end of treatment | 0.23 ± 1.27 | 0.16 ± 1.35 | ||||||
| BMI z scores, mean ± SD | 0.044 | 0.834 | ||||||
| Before methylphenidate | 0.28 ± 1.20 | 0.25 ± 1.23 | ||||||
| At the end of treatment | 0.08 ± 1.22 | 0.04 ± 1.26 | ||||||
ADHD-C, attention-deficit/hyperactivity disorder-continue; ADHD-DC, attention-deficit/hyperactivity disorder-discontinue; BMI, body mass index; n (number of patients), SD, standard deviation.
*All results were adjusted for age, the duration of treatment and the mean dosage of methylphenidate.
**The change in height was significant for treatment*age interacton (F = 12.487, p < 0.001).
***The change in height was moderated by the treatment*age (F = 6.976, p = 0.009) and treatment*mean dosage (F = 4.893, p = 0.027) interactions.
Treatment-related Factors and Growth Parameters
Table 4 represents the correlations between growth parameters and treatment-related factors. In patients in the ADHD-C group, statistically significant negative correlations were found between age at starting MPH and differences in weight SDS (r = −0.173, p = 0.005**) and height SDS between baseline and follow-up (r = −0.214, p** < 0.001). After adjustment for potential confounding factors (sex, age at starting treatment, the dosage of MPH, and duration of treatment) in multivariable linear regression analyses, only age at treatment start, predicted final weight-z score and BMI-z score at a statistically significant level (Table 5).
Table 4. Results of The Correlations between Growth Parameters and Treatment-Related Factors in the ADHD-C and ADHD-DC Groups.
| CORRELATIONS | DIF-HEIGHT | ADHD-C DIF-WEIGHT |
DIF-BMI | DIF-HEIGHT | ADHD-DC DIF-WEIGHT |
DIF-RMI | ||||||
| Age starting MPH-SDS | −0.214** (<0.001) | −0.173** (0.005) | 0.069 (0.266) | −0.009 (0.909) | −0.074 (0.340) | 0.031 (0.688) | ||||||
| Dosage of MPH [mg]-SDS | −0.005 (0.942) | −0.103 (0.095) | 0.033 (0.596) | −0.038 (0.627) | −0.126 (0.101) | −0.106 (0.169) | ||||||
| Duration of treatment-SDS | −0.061 (0.325) | 0.025 (0.688) | −0.031 (0.617) | −0.058 (0.451) | −0.102 (0.187) | −0.024 (0.757) |
ADHD-C, attention-deficit/hyperactivity disorder-continue; ADHD-DC, attention-deficit/hyperactivity disorder-discontinue; BMI, body mass index; MPH, methylphenidate; SDS, standard deviation score; Dif-BMI, difference between baseline and follow-up BMI, in SDS; Dif-Height, difference between baseline and follow-up height, in SDS; Dif-Weight, difference between baseline and follow-up weight, in SDS. *p < 0.05, **p < 0.01. p values from Pearson correlation test.
Table 5. Results of the Multiple Linear Regression Analysis model between the growth parameters and treatment-related factors (ADHD-C and ADHD-DC).
| MULTIPLE LINEAR REGRESSION | B | HEIGHT1 95% Cl |
P | B | WEIGHT1 95% Cl |
P | B | BMI1 95% Cl |
P | B | HEIGHT2 95% Cl |
P | B | WEIGHT2 95% Cl |
P | B | BMJ2 | P | ||||||||||||||||||
| Age at starting MPH | −0.170 | −0.705 to 0.364 | 0.531 | −0.192 | −1.940 to −0.445 | **0.002 | 1.146 | 0.410 to 1.883 | **0.002 | 0.007 | −0.052 to 0.066 | 0.807 | −1.035 | −1.926 to −0.144 | *0.023 | 0.871 | 0.062 to 1.680 | *0.035 | ||||||||||||||||||
| Dose of MPH [mg] | 1.403 | −0.535 to 3.341 | 0.155 | −3.114 | −5.825 to −0.403 | *0.025 | 1.819 | −0.852 to 4.490 | 0.181 | −0.026 | −0.266 to 0.215 | 0.833 | −1.547 | −5.187 to 2.093 | 0.403 | −0.114 | −3.419 to 3.190 | 0.946 | ||||||||||||||||||
| Duration of treatment | −2.427 | −5.924 to 1.070 | 0.173 | 2.388 | −2.504 to 7.280 | 0.337 | −0.905 | −5.724 to 3.915 | 0.712 | −0.059 | −0.342 to 0.223 | 0.680 | −3.856 | −8.131 to 0.419 | 0.077 | 2.611 | −1.270 to 6.491 | 0.186 | ||||||||||||||||||
| Sex | 0.001 | −0.087 to 0.089 | 0.990 | 0.033 | −0.145 to 0.097 | 0.599 | −0.024 | −0.145 to 0.097 | 0.697 | 0.003 | −0.007 to 0.012 | 0.552 | −0.001 | −0.144 to 0.141 | 0.986 | −0.052 | −0.182 to 0.078 | 0.429 |
1attention-deficit/hyperactivity disorder-continue; 2ADHD- attention-deficit/hyperactivity disorder-discontinue; BMI, body mass index; MPH, methylphenidate; SDS, standard deviation score; CI, confidence interval; *p<0.05, **p<0.01. p values from multiple linear regression test.
Discussion
This retrospective chart review analyzed the long-term effects of MPH discontinuation on the growth parameters of children and adolescents with ADHD. Continue and discontinue use of MPH in patients did not differ regarding main sociodemographic features, baseline growth parameters, daily MPH dosage, and treatment duration. Firstly, our results suggested there was no difference in terms of growth parameters between both groups when the discontinuation of MPH in children and adolescents. On the other hand, continued use of MPH was negatively correlated between age at starting MPH and differences in weight-z scores and height-z scores between baseline and follow-up.
Data on the effects of ADHD treatment discontinuation on growth remain limited. In most studies, although stimulants had some effect on growth, discontinuation of MPH was thought to compensate for this loss and contribute to the achievement of reference growth values.13,16 This is the basis for ‘drug holidays’ (stopping the use of stimulants during the planned and unplanned breaks from medication). These holidays may be prescribed by the clinician or may be taken by the parents or the patient on their own. This strategy was considered for different reasons, which can be used to control side effects, manage drug tolerance, or because of family desire. Some studies indicated a possible connection between drug holidays and the physiological changes in the growth parameters due to continuous MPH treatment. For example, a study on treatment discontinuation of stimulant drugs showed a positive impact on growth after a summer holiday.17 Another study conducted ten years later found that there was no group difference in height after one summer holiday’s discontinuation of treatment, but had a positive effect on height when MPH treatment was discontinued for two summer holidays.18 Likewise, in a recently published study conducted by Waxmonsky and colleagues (2020), results suggested the drug holidays led to increased weight velocity in children taking CNS stimulants, but no increased height velocity.13 In the current study, ADHD treatment discontinuation was not associated with any change in growth parameters between baseline and follow-up. Therefore, it appears that longer interruptions in medication use beyond limiting it to only school days or summer periods may be needed to meaningfully affect growth parameters. Moreover, other reasons for failure to detect diversities could include the timing of the pubertal growth spurt or duration of interventions.
The literature on the treatment of ADHD is generally based on the growth parameters and adverse effects of the drugs. However, the alterations of growth parameters like weight, height, and BMI may be associated with ADHD regardless of stimulant use. Some long-term follow- up studies reported significant growth suppression with continuous treatment,19–24 whereas others found no significant alterations.25,26 These effects might be explained by the fact that MPH increases dopamine levels, which inhibits gastric emptying and growth hormone, potentially explaining growth retardation.19,27 Alternatively, growth alterations in ADHD may be more related to the disorder itself rather than to the effects of treatment. These explanations might be clinically relevant because lower values of height and smaller head circumference are highly frequent in children with ADHD as compared to typically-developing controls.28
We report intriguing results about differential effects on that growth parameters by age group (e.g children vs. adolescents) and sex (e.g boys vs. girls). We observed statistically significant differences in weight z-scores and BMI z-scores of patients receiving continued or discontinued pharmacological treatment schemes. However, this effect was also shown in height z-scores of patients receiving ‘drug holidays’. These findings are partially consistent with other studies that have shown no impact of MPH on patients’ height.29,30 The differences in all studies could be interpreted due to different factors such as physical conditions, familial height, the normal variation of growth, medication dosage, and ‘drug holiday’ periods.31 Despite this limited knowledge, there could be a positive impact on child and adolescent height during the ‘drug holidays’. However, our results did not indicate the diverging results for continued and discontinued treatment schemas. On the other hand, considering whether patients were children or adolescents, the effects of treatment on height and weight were less clear when MPH was started during adolescence (Table S2). Based on these results, repeated measure ANOVA models also demonstrated the effect of MPH on height seems to be more pronounced in children than in adolescents. Taking into account this multivariate analysis, adjusted for potential confounding factors, the results suggest that age at treatment start is also important for final z scores of anthropometric measures. This is supported by the fact that the weight-reducing effects of stimulants could become less evident over time. However, as a major confounding variable, the nutritional status was not adequately reported to reach more conclusive results.
The main limitations of this study also need to be considered. First; this study was an observational retrospective chart review, which reduces its impact. Second, this study could not investigate the other psychopharmacological medications which also influence growth parameters due to the unavailability of data. This may have caused a selection bias. In addition, other individual variables with a potential effect on growth parameters (i.e., nutritional status, ethnicity, comorbidity, and developmental variations) were not recorded by authors.
Despite these limitations, our study has some strengths: 1) we aimed to eliminate possible confounding variables via statistical methods that could have influenced the results; so, anthropometric measurements could be obtained prior to treatment onset; 2) we evaluated the discontinue effect of MPH with the continuous effect of MPH that can be clinically important and which renders our results quite consistent.
The present study contributes valuable information about the long-term effects of methylphenidate discontinuation through ‘drug holidays’ on growth parameters. Our data showed that chronic use of MPH was likely responsible for changes in height and weight parameters. The clinical decision to discontinue treatment with MPH was not able to improve growth parameters in children and adolescents with ADHD. Following these findings, we suggest that growth parameters need to be continuously monitored when treating children and adolescents with MPH. Further studies comparing the long term impact of drug holidays of MPH on growth compared with healthy controls and other treatment regimes are required.
Footnotes
Funding
Not applicable.
Conflict interest
The authors declare no conflicts of interest.
Ethics approval
Ethical approval for this study was obtained from the Dokuz Eylul University Non Interventional Clinical Research Ethical Committee.
Consent to participate
Not applicable.
Consent for publication
Not applicable.
Availability of data and material
Supplemental material for this article is available online.
Code availability
Not applicable.
Authors’ contributions
ST, CE, MT: literature review, study design, data collection and analysis, and manuscript writing and review; VPS: manuscript review; AAP: study design, data collection, manuscript writing, and review.
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