Effects of Long-Term Use of Prescription Methylphenidate on Myocardial Performance in Children with Attention-Deficit/Hyperactivity Disorder: A Tissue Doppler Imaging Study

Abstract

Objective:

Many children diagnosed with attention-deficit/hyperactivity disorder are treated with methylphenidate (MPH). The purpose of this study was to evaluate the relationship between long-term use of osmotic-release oral system methylphenidate (OROS MPH) and cardiac functions.

Methods:

The study involved 116 subjects 6–18 years of age. Fifty-eight of these were in the case group and were using OROS MPH (extended-release capsules). Fifty-eight children not receiving treatment were included in the control group. Participants were also assessed using 12-channel electrocardiography (ECG), transthoracic 2D echocardiography, Doppler echocardiography, and tissue Doppler imaging (TDI). The findings obtained were compared using statistical methods.

Results:

No significant differences were determined between the case and control groups in terms of systolic blood pressure and diastolic blood pressure or 12-channel ECG findings. There was also no difference in 2D and M-mode measurements among the echocardiography findings. Of the TDI parameters obtained, only E′ septal values differed significantly between the case and control groups. However, this was not at such a level as to indicate cardiac function impairment.

Conclusions:

The study data showed that the echocardiographic parameters we measured resulted in no clinical difference between the children using MPH and the healthy controls. We conclude that MPH use in children does not impair cardiovascular functions at short-term follow-up.

Introduction

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder involving function impairment that commences before the age of 12 and is defined as the exhibition of symptoms of inattention, hyperactivity, and impulsivity in two or more settings (American Psychiatric Association 2013). The reported prevalence among school-age children varies between 5% and 10% in different studies (Scahill and Schwab-Stone 2000). Median age at onset of ADHD is 7–9 years, and 80% of lifetime ADHD is identified at 4–11 years (Kessler et al. 2007). Psychostimulants have been shown to be effective in treating ADHD in randomized controlled studies, and are widely used for this purpose. These are most commonly prescribed at the age of 5–11 years. Treatment rates with psychostimulants of 4.6% for children and 3.8% for adolescents have been determined (Sultan et al. 2018). The literature shows that school-age children are the group most commonly diagnosed with and treated for ADHD. Methylphenidate (MPH) is a psychostimulant frequently used in the treatment of ADHD (Remschmidt and Global and Working Group 2005).

There have been several case reports and studies concerning potential cardiac side-effects of MPH use. Statistically significant increases in blood pressure (BP) and heart rate (HR), but causing only minor clinical outcomes, have been reported in children diagnosed with ADHD and using MPH (Wilens et al. 2004). Use of stimulants among young people diagnosed with ADHD has been determined to increase the risks of emergency department visits and physician visits due to cardiac symptoms by 20% and 21%, respectively (Winterstein et al. 2007). There have also been reports of sudden cardiac death and cardiac function disorders with MPH use. It has also been reported that 1.8% of young people with sudden, unexplained mortality have taken stimulants, and particularly MPH. There is also thought to be a link between psychostimulant use and sudden, unexplained death among children and adolescents (Gould et al. 2009). Chest pains, increased cardiac biomarkers, acute left ventricular dysfunction, and pericarditis were reported in a 17-year-old adolescent following MPH use (Dadfarmay and Dixon 2009). A probable association was determined between MPH use and cardiomyopathy in an 18-year-old patient diagnosed with ADHD and treated with MPH (Concerta) (Nymark et al. 2008). Pulseless electrical activity and cardiac arrest have very rarely been reported among children during MPH therapy (Daly et al. 2008; Munk et al. 2015).

The high prevalence of ADHD among children and adolescents and high rates of treatment using drugs have raised concerns over cardiac effects of psychostimulants such as MPH. Cardiomyopathy, pericarditis, and loss of cardiac functions have largely appeared in the form of case reports. We also intended to investigate cardiac functions in patients using osmotic-release oral system methylphenidate (OROS MPH) (extended-release capsules). Our hypothesis was that cardiac function disorders would be at a higher level in children using MPH compared to those not using it.

Materials and Methods

The study was performed with 116 subjects, 58 children 6–18 years of age receiving MPH therapy, and 58 not receiving medication. Following receipt of ethics committee approval, the study was performed by the pediatric cardiology and child psychiatry clinics. The control group consisted of patients diagnosed with ADHD, but who had still not yet started taking medications. The case group consisted of patients diagnosed with ADHD at least 6 months previously and using MPH. The control group and case group were matched in terms of body surface area (BSA), weight, age, and sex. Subjects with known systemic disease, using drugs other than MPH, refusing to take part, or with other congenital or acquired heart diseases were excluded. Consent forms were read to all patients and their parents, and signed informed consent forms were obtained. A data form consisting of multiple choice questions and questions requiring written responses was prepared to elicit cases' sociodemographic and clinical characteristics. The forms were completed with the families.

Detailed patient and family cardiac histories were recorded and physical examination, BP, height, weight measurements, and 12-channel electrocardiography (ECG) records were taken. Transthoracic 2D echocardiography and conventional Doppler echocardiography were performed for all participants. All subjects also underwent clinical evaluations. Echocardiography was performed with subjects in the left lateral decubitus position using a GE Vivid 7 Ultrasound device (GE Medical Systems, Horten, Norway) and a 2.5–3.5 MHz transducer with a transthoracic approach in both groups. Following echocardiographic evaluation, BP was measured using a sphygmomanometer by placing a cuff appropriate to the subject's age on the right arm. Phase 1 and phase 5 Korotkoff sounds were monitored as systolic BP (SBP) and diastolic BP (DBP). SBP and DBP values were obtained by taking the averages of three measurements. Twelve-lead ECG was evaluated for arrhythmia. A corrected QT interval (QTc) was calculated using the formula corrected QT (QTc) = QT/√R − R. Values exceeding 0.44 seconds were regarded as prolonged.

Echocardiographic measurements: echocardiographic measurements were performed using 2D echocardiography, conventional Doppler echocardiography, and tissue Doppler echocardiography (tissue Doppler imaging [TDI]). The left atrium (LA) was visualized using the parasternal long axis, and left ventricular functions were measured on the parasternal long axis using M mode by 2D echocardiography. Interventricular septum end-systolic and end-diastolic diameter (IVSs and IVSd), left ventricular end-systolic and end-diastolic diameter (LVEDs and LVESd), left ventricular posterior wall end-systolic and end-diastolic diameter (LPWDs and LPWDd), left ventricular ejection fraction (LVEF), and left ventricular fractional shortening (LVFS) were calculated.

Conventional Doppler Measurements and TDI: acquisition by pulsed TDI was recorded at a high frame rate (>180 fr/s) at apical four-chamber imaging for the mitral annulus. An appropriate velocity scale was chosen to avoid data aliasing. The narrowest image sector angle possible (usually 30°) was used to achieve the maximum possible color Doppler frame rate. Mitral early diastolic flow velocity (E), its decreasing time (EDT), and late diastolic flow velocity (A) and its duration time (A time), and the E/A ratio were measured with a sample volume of PW placed at the level of the mitral annulus in apical four-chamber view. The sample volume was placed at the conjunction of the septal and lateral wall of the left ventricle and mitral annulus. Peak early diastolic wave velocity septal and lateral (E′ septal and E′ lateral), peak late diastolic wave velocity septal and lateral (A′ septal and A′ lateral), isovolumetric relaxation time septal and lateral (IVRT septal and IVRT lateral), peak systolic wave velocity septal and lateral (S′ septal and S′ lateral), and isovolumetric contraction time septal and lateral (IVCT septal and IVCT lateral) were measured using TDI on both the septal and lateral parts of the mitral annulus to elicit data for LV diastolic functions.

Descriptive statistics were used to describe constant variables (mean, standard deviation, minimum, median, and maximum). The Mann–Whitney U test was used to compare two independent variables not exhibiting normal distribution and Student's t-test to compare normally distributed independent variables. The chi-square test (or Fisher's exact test where appropriate) was used to compare categorical variables. Statistical significance was set at 0.05. Analyses were carried out on MedCalc Statistical Software version 12.7.7 (MedCalc Software bvba, Ostend, Belgium; www.medcalc.org; 2013).

Results

Fifty-eight subjects using OROS MPH were included in the case (patient) group. The mean age of the case group was 10 years, the youngest being 7 and the oldest 18. Patients' weights ranged between 25 and 87 kg, with a mean weight of 42.57 kg. Height measurements ranged between 122 and 180 cm, with a mean value of 146.8 cm. Both the case and control groups consisted of 45 boys and 13 girls. The control group was constituted such as to match the control group. No significant difference was present between the groups in terms of BSA, height, weight, age, sex distribution, and family cardiac history (Table 1). Mean duration of MPH use was 2.73 years. The mean MPH dosage was 39.41 mg and 0.93 mg/kg (max: 1.42 mg/kg and min: 0.56 mg/kg).

Table 1.

A Comparison of Demographic Data and Electrocardiography Findings in the Case and Control Groups

	Case group n = 58	Control group n = 58
	Mean ± SD Median (min-max)	Mean ± SD Median (min-max)	p
Age (years)	10.78 ± 2.78	10.05 ± 2.98	0.06^a
Age (years)	10 (7–18)	9 (6–17)	0.06^a
Weight (kg)	42.57 ± 13.76	41.48 ± 14.62	0.4^a
Weight (kg)	38 (25–87)	36 (24–84)	0.4^a
Height (cm)	146.8 ± 14.07	144.4 ± 15.17	0.327^a
Height (cm)	144 (122–180)	139.5 (116–185)	0.327^a
Body surface area (m²)	1.31 ± 0.26	1.28 ± 0.28	0.347^a
Body surface area (m²)	1.25 (0.95–2)	1.18 (0.88–2.02)	0.347^a

	n (%)	n (%)
Sex
Male	43 (74.1)	43 (74.1)	1.00^b
Female	15 (25.9)	15 (25.9)	1.00^b
Cardiac history in the family
No	39 (67.2)	41 (70.7)	0.841^b
Yes	19 (32.8)	17 (29.3)	0.841^b
QTc (s)	0.39 ± 0.02	0.39 ± 0.03	0.106^c
QTc (s)	0.39 (0.34–0.44)	0.4 (0.33–0.44)	0.106^c
HR (beat/min)	84.41 ± 14.96	82.16 ± 13.26	0.562^c
HR (beat/min)	85 (47–115)	83.5 (49–113)	0.562^c
SBP (mmHg)	104.09 ± 11.14	106.72 ± 10.88	0.180^a
SBP (mmHg)	100.5 (90–129)	107.5 (85–128)	0.180^a
DBP (mmHg)	63.97 ± 7.66	63.79 ± 9.26	0.723^a
DBP (mmHg)	60 (49–80)	65 (41–84)	0.723^a

Mann–Whitney U test.

Fisher's exact test.

Student's t-test.

DBP, diastolic blood pressure; HR, heart rate; QTc, corrected QT interval; SBP, systolic blood pressure.

No significant differences were determined between the case and control groups in terms of SBP and DBP or 12-channel ECG findings (Table 1). There was also no difference in 2D or M-mode measurements among the echocardiographic findings (Table 2).

Table 2.

A Comparison of Echocardiographic Data in the Case and Control Groups

	Case group n = 58	Control group n = 58
	Mean ± SD Median (min-max)	Mean ± SD Median (min-max)	p
IVSd (cm)	0.77 ± 0.14	0.74 ± 0.13	0.326
IVSd (cm)	0.8 (0.5–1.2)	0.7 (0.5–1)	0.326
LVEDd (cm)	4.02 ± 0.5	4.05 ± 0.5	0.771
LVEDd (cm)	4 (3–5.3)	4 (3.2–5.2)	0.771
LPWDd (cm)	0.73 ± 0.14	0.72 ± 0.12	0.668
LPWDd (cm)	0.7 (0.5–1.1)	0.7 (0.5–1)	0.668
IVSs (cm)	0.99 ± 0.18	0.98 ± 0.15	0.940
IVSs (cm)	1 (0.7–1.4)	1 (0.7–1.4)	0.940
LVESd (cm)	2.45 ± 0.37	2.43 ± 0.45	0.488
LVESd (cm)	2.43 (1.7–3.5)	2.35 (1.7–3.7)	0.488
LPWDs (cm)	1.05 ± 0.43	0.98 ± 0.16	0.377
LPWDs (cm)	1 (0.7–4)	0.98 (0.7–1.3)	0.377
LVEF (%)	70.62 ± 4.53	72.17 ± 4.4	0.051
LVEF (%)	70 (62–86)	72 (65–82)	0.051
LVFS (%)	39.83 ± 3.93	40.95 ± 3.8	0.098
LVFS (%)	39 (34–55)	41 (35–51)	0.098
LA diameter (cm)	2.42 ± 0.31	2.3 ± 0.28	0.056
LA diameter (cm)	2.4 (1.9–3.2)	2.3 (1.8–3)	0.056

Mann–Whitney U test.

IVSd, interventricular septum end-diastolic diameter; IVSs, interventricular septum end-systolic diameter; LA, left atrium diameter; LPWDd, left ventricular posterior wall end-diastolic diameter; LPWDs, left ventricular posterior wall end-systolic diameter; LVEDd, left ventricular end-diastolic diameter; LVESd, left ventricular end-systolic diameter; LVEF, left ventricular ejection fraction; LVFS, left ventricular fractional shortening.

No differences were observed among the mitral valve Doppler parameters E, A, E/A, EDT, and A wave duration, or among the tissue Doppler parameters E′ lateral, A′ septal and lateral, S′ septal and lateral, IVRT septal and lateral, and IVCT septal and lateral. However, a statistically significant difference was observed between case and control group E′ septal values (p = 0.026). E′ septal values were lower in patients using MPH than in the control group (Table 3).

Table 3.

A Comparison of Doppler and Tissue Doppler Parameters in the Case and Control Groups

	Case group n = 58	Control group n = 58
	Mean ± SD Median (min-max)	Mean ± SD Median (min-max)	p
E (cm/s)	100.06 ± 15.55	101.43 ± 17.41	0.899
E (cm/s)	102 (59.4–134)	100 (62–144)	0.899
A (cm/s)	52.44 ± 10.75	55.43 ± 11.92	0.282
A (cm/s)	52.65 (34–77.1)	54 (33–100)	0.282
E/A	1.96 ± 0.42	1.89 ± 0.44	0.449
E/A	1.99 (1.12–3.02)	1.89 (1.04–2.89)	0.449
EDT (ms)	112.28 ± 17.47	106.22 ± 18.28	0.077
EDT (ms)	110.71 (86–173.7)	105.36 (68.39–151)	0.077
A wave duration (ms)	113.76 ± 17.66	111.59 ± 21.07	0.202
A wave duration (ms)	111.88 (85.03–172)	107 (81.33–199)	0.202
S′septal (cm/s)	7.78 ± 1.88	9.32 ± 8.21	0.347
S′septal (cm/s)	8 (0.07–11.2)	8 (6.96–70)	0.347
E′ septal (cm/s)	14.43 ± 2.48	15.44 ± 2.24	0.026
E′ septal (cm/s)	14.85 (9.25–20)	15 (10–20)	0.026
A′ septal (cm/s)	6.76 ± 1.28	7.11 ± 1.52	0.172
A′ septal (cm/s)	6.19 (4–10.5)	7 (5–15)	0.172
IVCT septal (ms)	55.32 ± 7.67	55.1 ± 9.31	0.971
IVCT septal (ms)	55 (40.67–75.63)	55.45 (31.42–90.57)	0.971
IVRT septal (ms)	56.3 ± 10.51	53.56 ± 7.03	0.187
IVRT septal (ms)	55.45 (35.12–85.03)	53.6 (35.12–68.39)	0.187
S′ lateral (cm/s)	10.98 ± 2.38	10.63 ± 2.37	0.920^a
S′ lateral (cm/s)	11 (6–17)	10.15 (6–16)	0.920^a
E′ lateral (cm/s)	19.47 ± 4.07	19.99 ± 3.14	0.535
E′ lateral (cm/s)	19 (10.5–27)	19 (14.8–27.9)	0.535
A′ lateral (cm/s)	7.18 ± 1.49	6.84 ± 1.72	0.136
A′ lateral (cm/s)	7 (4–11)	6.98 (4–14)	0.136
IVCT lateral (ms)	54.61 ± 12.24	54.61 ± 9.89	0.689
IVCT lateral (ms)	51.76 (36.97–110.91)	53.33 (36.97–77.63)	0.689
IVRT lateral (ms)	55.58 ± 10.98	52.26 ± 8.74	0.118^a
IVRT lateral (ms)	55.23 (29.57–83)	51.76 (33.27–77.63)	0.118^a
E/E′	7.09 ± 1.43	6.65 ± 1.26	0.099
E/E′	6.93 (4.38–11.6)	6.51 (4.3–9.64)	0.099

Numbers in bold text denote significant differences (p < 0.05).

Student's t-test. Mann–Whitney U test.

A, peak late diastolic wave velocity; A′, peak velocity of late diastolic mitral annular motion; E, peak early diastolic wave velocity; E′, peak velocity of early diastolic mitral annular motion; EDT, E wave deceleration time; IVCT, isovolumetric contraction time; IVRT, isovolumetric relaxation time.

Discussion

MPH derivatives are frequently prescribed as a component of treatment in ADHD. The use of these drugs is growing continually. While drug therapy provides significant clinical benefits, there are, nevertheless, concerns regarding its safety. We assessed use-related echocardiographic parameters in children capable of tolerating MPH, benefiting from treatment, and with long-term use. No significant difference was determined between the case and control groups in any cardiac parameter measured with the exception of E′ septal values. These E′ septal values indicated no cardiac dysfunction in our case group. Our data show that MPH use does not lead to cardiac function disorder in children. Our study hypothesis that cardiac function disorders would be at a higher level in children using MPH compared to those not using it was thus refuted.

MPH dose-dependently increases extracellular dopamine (DA) and norepinephrine (NE) indirectly by blocking the DA and NE transporters, DAT and NET (Jenson et al. 2015). This causes an increase in the synaptic concentration of DA and NE acting as a catecholaminergic agonist. The mechanism in cardiovascular toxicity deriving from MPH is thought to be particularly associated with excessive extracellular DA and NE (Spiller et al. 2013). MPH is thought to be capable of raising cardiac rhythm and causing increases in BP with its dopaminergic effects, and this is believed to partially mediate central dopaminergic effects and DA-related increases in peripheral epinephrine (Volkow et al. 2003; Take et al. 2008). Studies investigating cardiovascular risk associated with MPH use in children have observed elevations in SBP, DBP, and HR with drug therapy (Samuels et al. 2006; Ilgenli et al. 2007; Hammerness et al. 2009; Yildiz et al. 2011). Several studies of the cardiac effects of drugs used in the treatment of ADHD have reported small increases in mean HR and BP in MPH users. However, these increases were not statistically significant in most studies (Stiefel and Besag 2010; Awudu and Besag 2014). In this study, we determined no significant increase or difference between our case and control groups' SBP and DBP results. BP and HR values were unaffected in patients with good medication tolerance and using appropriate dosages.

We determined no difference in corrected QT interval (QTc) values between subjects using MPH and those not using it. Previous studies have reported differing results for QTc values. One study of MPH use over 8 weeks determined post-treatment QTc prolongation (Snircova et al. 2018). There is a known increased risk of arrhythmia with MPH therapy in children and young people with ADHD (Shin et al. 2016). In contrast, other studies have determined no significant statistical or clinical variation at analysis of ECG results and QTc (Kratochvil et al. 2002; Hammerness et al. 2009). We also determined no significant statistical or clinical variation at ECG and QT intervals.

Cases have been reported involving findings of mild or severe heart failure in patients presenting to hospital with cardiac symptoms when using MPH. Coronary vasospasm and decreased LVEF were determined in one reported case (Baumeister et al. 2016). Dilated left ventricle and a very low ejection fraction (EF = 25%) were determined with echocardiographic study in another case (Nymark et al. 2008). In contrast, one previous study evaluating the cardiac safety of MPH determined that exposure to MPH represented an increased risk for heart failure (Shin et al. 2016). EF values in our study were within normal limits, and no heart failure findings were determined in our subjects.

Although there have been reports about cardiovascular dysfunction associated with MPH in the literature, in our study there was no significant difference between case and control groups in terms of echocardiographic parameters except E′ septal value. Our review of the literature revealed no previous studies investigating the relationship between MPH and E′ septal. E′ septal values were lower in the case group in our study. The early diastolic velocity of the mitral valve annulus (E′) reflects the rate of myocardial relaxation (Hillis et al. 2004). MPH is thought to be capable of increasing cardiac contraction through its dopaminergic effects. One study in which rats were given MPH showed a dose-dependent increase in D2 expression in myocytes in cardiac tissue (Take et al. 2008). DA has also been shown to be capable of causing an increase in left ventricular filling pressure. Arterial vasoconstriction linked to alpha-adrenoceptor activation has been proposed as the mechanism responsible for the increased left ventricular filling pressure observed with DA (Lang et al. 1988). A decrease in E′ septal values may probably be seen with the peripheral effects of MPH. The ratio (E/E′) obtained when combined with early transmitral flow velocity (E) measurement exhibits good correlation with mean left ventricular diastolic pressure (LVDP) (Hillis et al. 2004). The E/E′ ratio is used to predict risk in patients with adult cardiac pathologies, the risk rising as the ratio increases (Sharp et al. 2010). The E/E′ ratio has recently been reported to be the most accurate predictor of high left ventricular filling pressures. The ratio is also particularly recommended for use in estimating left ventricular filling pressures in patients with preserved systolic function. Patients with E/E′ ratios >15 are classified as having elevated filling pressures (Ommen et al. 2000). However, these ratios in the literature were obtained from adult studies. There are no E′ and E/E′ reference ranges for children, which vary with age and are supported by studies, but when this figure exceeds 15 in adults patients, this is regarded as a predictor of diastolic dysfunction. The ratio did not exceed 15 in any of the subjects in our case group. Other parameters capable of suggesting diastolic dysfunction, such as E, A, E/A, EDT, A time, and IVRT, were similar in our patients to those in the control group. In addition, no statistically significant difference was determined between our case and control groups in terms of mean E/E′ values. Our finding when all the parameters are analyzed together does not indicate cardiovascular function impairment. In conclusion, we do not think that our E′ septal values can be used to indicate cardiovascular function disorder.

Our review of the literature revealed studies indicating that MPH poses no or little risk in terms of cardiovascular effects. Wide sample retrospective cohort studies have concluded that there is no relationship between serious cardiovascular events and the use of drugs, including MPH in the treatment of ADHD in pediatric and adult patients (Cooper et al. 2011; Habel et al. 2011). Six out of seven community-based observational studies involving children and adolescents reported no link between prescription stimulant use and undesirable cardiovascular outcomes (Westover and Halm 2012). Long-term cardiovascular risks for adult with ADHD and healthy children have been limited to minor mean increases in BP and HR, and while subjective symptoms may be anticipated during long-term treatment, there is no increase in severe cardiac outcomes (Hammerness et al. 2015; Hennissen et al. 2017). In agreement with these previous studies, we also conclude that MPH use involves no cardiovascular risk.

Since we enrolled patients with long-term drug use, our study group patients were well able to tolerate the medication. Our study measured cardiac parameters only for patients maintaining drug use. MPH users unable to maintain treatment or with severe cardiac symptoms were not evaluated in this study.

Conclusion

With the exception of E′ septal values, no significant difference was determined in this study between the case and control groups in terms of any of the parameters investigated. The E′ septal values observed were also within normal limits and did not indicate cardiac function disorder. Our study shows that long-term use does not lead to cardiac function impairment in children experiencing tolerable side-effects and using prescribed OROS MPH in appropriate doses.

Clinical Significance

This is the first study which compares cardiac functions of children taking OROS MPH with healthy controls by using transthoracic 2D echocardiography, Doppler echocardiography, and tissue Doppler imaging. The only difference between the groups was E′ septal values, however this difference was not clinically significant. The results of this study showed that using OROS MPH in children under the supervision of a clinician does not lead to negative cardiac consequences.

Footnotes

Acknowledgment

We are grateful to the patients and controls for their participation.

Disclosures

The authors declare that they have no conflict of interests with regard to this work. The authors alone are responsible for the content and writing of the article.

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