The Effect of Methylphenidate Treatment on Heart Rate Variability and Cardiac Autonomic Functions in Children with Attention Deficit Hyperactivity Disorder

Özgür KIZILCA; Saliha BAYKAL

doi:10.4274/nkmj.galenos.2023.38257

ABSTRACT

Conclusion:

Our study showed that there was increased sympathetic and decreased parasympathetic activity in HRV parameters in ADHD patients. Both sympathetic and parasympathetic improvement was observed with MPH treatment. Although our study shows that MPH treatment has a curative effect on cardiac autonomic functions, further studies are needed.

Results:

There was no difference in age, gender, weight and height in the patient and control groups (p>0.05). In the analysis of time-dependent HRV parameters, SDNN, SDANN, which shows the sympathetic influence, and rMSSD, which shows the parasympathetic influence, were statistically significantly lower in the patient group than in the control group (p<0.05). When the patients were compared before and after the treatment, SDANN increased statistically (p<0.05). Besides, SDNN and rMSSD increased after the treatment, although there was no statistical significance (p>0.05).

Materials and Methods:

We used a retrospective pre-post treatment study design to measure the change in HRV parameters in ADHD patients receiving MPH therapy. A total of 49 patients (mean age, 8.3±2.5 years) diagnosed with ADHAB and 30 sex- and age-matched healthy controls (mean age, 8.2±2.7 years) were examined. Rhythm Holter recordings were made for the patients before MPH treatment and in the first month of treatment and for the control group, and HRV parameters were evaluated in the computer environment.

Aim:

Attention deficit hyperactivity disorder (ADHD) is the most common childhood psychiatric disorder. Psychostimulant drugs are frequently used in the treatment regimen. The possible cardiac side effects of drugs are of concern. In our study, we aimed to determine possible cardiac autonomic effects with heart rate variability (HRV) in ADHD patients receiving methylphenidate (MPH).

Keywords:

Attention deficit hyperactivity disorder, methylphenidate, heart rate variability

INTRODUCTION

Attention deficit and hyperactivity disorder (ADHD) is the most common neuropsychiatric disease of childhood with a rate of 9.5% in school-age children^1,2.

As ADHD causes difficulties in social and academic development in children, they also face risks such as neuropsychiatric diseases, substance abuse, and increased delinquency in adulthood³.

The presence of hypofunction in the prefrontal cortex in the central nervous system (CNS) has been shown in the neuropathology of the disease. Different regions of the prefrontal cortex have regulatory effects on motor, sensory, behavioral and autonomic functions^4,6. Therefore, hypofunction in the prefrontal cortex was thought to be the cause of symptoms in patients with ADHD^5,6.

The two main components of treatment are behavioral therapy and psychostimulant pharmacotherapy. Behavioral therapy is the first thing to be done, but it is often the first choice because of faster and more effective results with medical treatment^7-9. While 50% of children with ADHD receive behavioral therapy, 75% receive psychostimulant treatment^9,10. These drugs exert stimulating effects on the CNS by increasing the levels of norepinephrine and dopamine in the prefrontal cortex¹¹. Methylphenidate (MPH) is the most used psychostimulant drug¹².

Psychostimulant drugs may cause cardiac risks such as the prolongation of cQT duration, arrhythmia and hypertension, and sudden death due to drug use has been reported^13,14. However, this situation is controversial and some studies have not found a significant difference in terms of cardiac risks^15,16. This may be due to the fact that the patients receiving medical treatment are children and adolescents who are cardiac healthy, and the publications are often of short duration⁹. However, in order to minimize the ultimate risks, guidelines recommend taking history, physical examination, and pre-treatment electrocardiography in evaluation¹⁷.

Heart rate variability (HRV) in 24-hour rhythm Holter is defined as the change in heart rate from beat to beat and shows the dynamic interaction of the sinoatrial node with the autonomic nervous system (ANS)⁶. It is a simple and non-invasive method to examine the effect of ANS on the cardiovascular system (CVS)⁶. HRV is an indicator of central-peripheral neural feedback and CNS-ANS integration, and respiratory sinus arrhythmia is considered an index of cardiac vagal modulation and emotional regulation^18-20. The standard deviation of normal sinus RR intervals (SDNN) and the standard deviation of the averages of five-minute recordings over twenty-four hours (SDANN) in the HRV analysis reflects sympathetic modulation, while the root mean square of the difference between consecutive normal RR intervals (rMSSD) and the percentage of consecutive normal sinus RR intervals that differ by more than 50 ms (pNN50) reflect parasympathetic modulation. HRV studies of ADHD show the presence of autonomic dysfunction, but the results are confusing. Although there are studies showing an increase in parasympathetic (vagal) tone, there are studies showing a decrease in vagal tone on the contrary^6,11,21.

Examination of the presence of autonomic dysfunction in children with ADHD may be useful both for a better understanding of neurobiology and for identifying patients who may be at risk for CVS⁶. As a result, treatment planning and follow-up can be done more carefully in patients at risk⁶.

The aim of this study is to compare HRV with the healthy control group, assuming that children with ADHD show autonomic dysfunction, and to investigate the effect of psychostimulant MHP used in the treatment on HRV and therefore on autonomic dysfunction.

GİRİŞ

Dikkat eksikliği ve hiperaktivite bozukluğu (DEHB) okul çağındaki çocukluklarda %9,5 oranında görülen, çocukluk çağının en sık görülen nöropsikiyatrik hastalığıdır^1,2.

DEHB, çocuklarda sosyal ve akademik gelişiminde zorlanmaya neden olduğu gibi erişkin yaşta da benzer nöropsikiyatrik hastalıklar, madde bağımlılığı, suç meyilinde artış gibi risklerle karşı karşıya kalırlar³.

Hastalığın nöropatolojisinde santral sinir sisteminde (SSS) prefrontal kortekste hipofonksiyon varlığı gösterilmiştir. Prefrontal korteksin farklı bölgeleri motor, duysal, davranışsal ve otonom fonksiyonlar üzerine düzenleyici etki gösterir^4,6. Bu yüzden prefrontal korteksteki hipofonksiyon DEHB olan hastalarda semptomların nedeni olabileceği düşünülmüştür^5,6.

Tedavinin ana iki bileşeni davranış terapi ve psikostimülan farmakoterapidir. Davranış terapi ilk yapılması gereken olmakla birlikte sıklıkla medikal tedavi ile daha hızlı ve etkili sonuçlar alınmasından dolayı ilk tercih edilendir^7-9. DEHB alan çocukların %50’si davranış terapi görürken, %75’i psikostümülan tedavi almaktadır^9,10. Bu ilaçlar prefrontal kortekste nöradrenalin ve dopamin seviyelerini artırarak SSS üzerine uyarıcı etkiler gösterirler¹¹. DEHB prevalansı aynı kalmakla birlikte ilaç kullanımı son on yılda %26 oranında artmıştır¹¹. Psikostimülan ilaçlardan en sık metilfenidat (MPH) kullanılır¹².

Psikostimülan ilaçlar cQT süresinde uzama, aritmi, hipertansiyon gibi kardiyak risklere neden olabildiği gibi ilaç kullanımına bağlı ani ölümler bildirilmiştir^13,14. Ancak bu durum tartışmalıdır ve yapılan bazı çalışmalarda kardiyak riskler açısından anlamlı fark bulunmamıştır^15,16. Bunun sebebi medikal tedavi alan hastaların kardiyak açıdan sağlıklı olan çocuk ve adelosan olması ve yayınların sıklıkla kısa süreli olmaları olabilir⁹. Ancak nihai riskleri en aza indirmek için kılavuzlar değerlendirmede öykü fizik muayene ve tedavi öncesi Elektrokardiyografi incelemesi önermektedir¹⁷. Çocuklarda yapılmış uzun süreye yayılmış birkaç çalışmada aritmi, hipertansiyon, kardiyak semptomlarla (çarpnıtı, senkop, göğüs ağrısı gibi) acile başvuru riskinde artış saptanmıştır. Özelikle altta yatan kardiyak hastalık varlığında bu risk artmaktadır⁹.

Yirmi dört saatlik ritm Holterde kalp hızı değişkenliği (HRV), kalp hızının atımdan atıma değişimi olarak tanımlanır ve sinoatrial düğümün otonom sinir sistemi (OSS) ile dinamik etkileşimini gösterir⁶. Kardiyovasküler sistem (KVS) üzerine OSS etkisini incelemek için basit ve non-invaziv bir yöntemdir⁶. HRV merkezi-çevresel nöral geri bildirim ve SSS-OSS entegrasyonunun bir göstergesidir ve solunumsal sinüs aritmisi, kardiyak vagal modülasyonun ve duygusal düzenlemenin bir indeksi olarak kabul edilir^18-20. HRV analizinde normal sinüs RR aralarının standart sapması (SDNN) sempatik modülasyonu yansıtırken, ardışık normal RR aralığı farkının ortalama karekökü (rMSSD) ve 50 ms’den fazla farklılık gösteren ardışık normal sinüs RR aralıklarının yüzdesi (pNN50) parasempatik modülasyonu yansıtır. DEHB yapılan HRV çalışmaları otonom disfonksiyon varlığını göstermekle birlikte sonuçlar kafa karıştırıcıdır. Parasempatik (vagal) tonus artışının gösterildiği çalışmalar olmakla birlikte tam tersine vagal tonus azalmasının olduğu çalışmalarda mevcuttur^6,11,21.

DEHB olan çocuklarda otonomik disfonsiyonun varlığının incelenmesi hem nörobiyolojinin daha iyi anlaşılmasını hem de KVS risk altında olabilecek hastaların belirlenmesi için faydalı olabilir⁶. Bunun sonucunda risk altındaki hastalarda tedavi plan ve takibi daha dikkatli yapılabilir⁶.

Bu çalışmanın amacı DEHB olan çocukların otonomik disfonskiyon gösterdiğini var sayarak sağlıklı kontrol grubu ile HRV’yi karşılaştırmak ve tedavide kullanılan psikostimülan MHP’ın HRV’ye, dolasıyla otonom disfonksiyon üzerine etkisini araştırmaktır.

MATERIALS AND METHODS

Patients who applied to Tekirdağ Namık Kemal University Medical Hospital Child and Adolescent Psychiatry outpatient clinic for the first time between 1^st of January, 2018 and 31^th of December, 2020 and who were diagnosed with ADHD according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria were included in this retrospective study²². Forty-nine patients (38 boys and 11 girls, mean age 8.31±2.53 years, between 6-17 years of age) who were referred to the Pediatric Cardiology outpatient clinic were included. Chronic disorders of the CVS, pulmonary and/or other systems, hypertension, intolerance of MPH, not taking MPH for two days or longer, drug use affecting CVS and CNS, psychotic disorder and mental retardation were used as exclusion criteria. The study was planned on three groups. While the first group included the patients diagnosed with ADHD before the treatment, the patients who were started on long-acting MPH therapy and evaluated in the first month of the treatment constituted the second group. The third group consisted of 30 age- and sex-matched healthy volunteers (21 boys and 9 girls, mean age 8.20±2.76 years, 6-17 years of age) who did not have any psychiatric disease, did not use drugs, and applied to the pediatric cardiology outpatient clinic due to an innocent murmur. For routine evaluation, physical examination, blood pressure, electrocardiography, and echocardiography were performed on the patient and control group. Twenty-four-hour rhythm Holter examination was performed twice, before the treatment and in the control examination in the first month of the treatment.

The patient group was assigned to one of three dose levels per day (10, 18, or 27 mg) based on long-acting MPH doses. Initial treatment of MPH was given at a dose of 0.3-0.6 mg/kg/day. In the second Holter treatment, the patients were inserted in the first month without increasing the dose. While rhythm Holter was inserted in 41 patients before the treatment, rhythm Holter control was performed in 27 patients in the first month of the treatment.

The study approval was obtained from the ethics committee of Tekirdağ Namık Kemal University non-interventional clinical studies (2021.189.06.19) and was conducted in accordance with the Declaration of Helsinki and Good Clinical Practices (date: 12.11.2020, no: 2020/68).

Echocardiographic Studies

Echocardiographic examinations were performed using a 4V1c transducer with an ultrasound device (ACUSON SC2000, Siemens, Germany). Transthoracic echocardiography images were obtained in parasternal long-axis and short-axis images, and apical two- and four-chamber views using standard transducer positions. The following end-diastolic and end-systolic parameters were measured in parasternal long-axis view on M-mode echocardiography: interventricular septal thickness (IVSd and IVSs), LV dimensions (LVDd and LVDs), and LV posterior wall thickness (LVPWd and LVPWs) left ventricular ejection fraction (Ef) and fraction shortening (Fs).

Processing and Analysis of 24-hour Holter Recordings

While the patient and control groups continued their normal daily lives, rhythm recordings were made with a three-channel (medilogFD12 plus, Schiller, Switzerland) rhythm Holter monitor for 24 hours. All Holter recordings were reviewed by an experienced cardiologist after artifact recordings were deleted. HRV parameters were analyzed in a computer program. Physiological interpretation and measurement of HRV parameters were performed according to the standards set by the Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology²³.

The time domain measurement of HRV determines the heart rate at any time point or the intervals between successive normal complexes. Each QRS complex is detected on the ECG, and then all intervals (NN/normal to normal intervals) between adjacent QRS complexes resulting from sinus node depolarization and instantaneous heart rate are determined. HRV measurements were calculated using normal-to-normal ranges only. SDNN, SDANN, SDNN index, RMSSD, NN50 and pNN50 were calculated in time-based HRV parameters. SDNN (ms): the standard deviation of the time (NN interval) between consecutive normal QRS complexes. SDANN (ms): the standard deviation of the averages of five-minute recordings over twenty-four hours. SDNN index (ms): the arithmetic mean of the standard deviations of the NN intervals of five-minute recordings over twenty-four hours. RMSSD (ms): the square root of the mean of the difference of the adjacent NN intervals in a 24-hour recording. NN50: the number of intervals in which the difference between consecutive NN intervals is greater than 50 ms. pNN50 (%): the ratio of the number of NN50 to the total number of NN intervals²³.

SDNN is used for the general evaluation of HRV, SDANN is used for the long-term evaluation of HRV and it reflects the effect of the sympathetic system on HRV, while rMSSD and pNN50 for the short-term evaluation reflect the effect of the parasympathetic system on HRV²³.

Statistical Analysis

Statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) software, version 22.0 (SPSS Inc.IL, USA). Continuous data were indicated as mean±standard deviation, while categorical data were presented as the number of patients. The chi-square test was used to compare categorical variables, while parametric continuous variables were compared using the Student’s t-test. Data were checked for normal distribution using the Kolmogorov-Smirnov test. The correlation between two variables was calculated using the Pearson’s correlation coefficient (r) analysis of variance (F). A value of p<0.05 was considered statistically significant.

RESULTS

Cohort Characteristics

A total of 49 patients with ADHD (mean age was 8.3±2.5 years; 38 boys and 11 girls) and 30 healthy controls (mean age was 8.2±2.7 years; 21 boys and 9 girls) were enrolled in this study. No significant differences were found between the two groups in terms of age, sex, weight, blood pressure systole and diastole, left ventricular end-diastolic dimension and ejection fraction (p>0.05). In the patient group, the MPH dose was 0.57±0.15 mg/kg/day. Table 1 shows the characteristics of the patient and the control groups.

Heart Rate Variability Findings

Analysis of the HRV data of the groups (Table 2) did not show any significant difference between the patient and control groups in terms of heart rate, Mean NN, SDANN index, NN50 and pNN50 (p>0.05). However, SDNN, SDANN and rMSSD were significantly lower in the patient group compared to the control group (p<0.05).

When HRV parameters in ADHD patients were compared between the pre- and post-treatment groups (Table 3), there was statistically significantly higher SDANN in the post-treatment group than in the pre-treatment group (p²<0.05). There was no difference in other HRV parameters between the two groups. In addition, when we compared the post-treatment group with the control group, there was no difference between HRV parameters (p¹>0.05).

In the correlation analysis between age and MPH dose and HRV parameters (Table 4), there was no correlation between MPH dose and HRV parameters (p>0.05), there was a negative correlation between age and heart rate and a positive correlation between age and mean NN (p<0.05).

Study Power

The power results calculated according to the effect size values found using the numerical data of SDANN, SDANN and rMSSD in the available sample size using G*Power 3.1.9.2 software were 85%, 94%, 95% for SDNN, SDANN and rMSSD in the patient-control group, respectively. In addition, the power result was 81% for SDANN in the pre- and post-treatment group.

DISCUSSION

In the treatment of ADHD, the first treatment option is often the use of psychostimulant drugs such as MPH. In recent years, there has been concern about the possible CVS side effects of psychostimulant drugs. Studies on this subject are quite confusing as to whether psychostimulant drugs have a positive or negative effect on CVS. In our study, we aimed to investigate the potential benefit-harm relationship of MPH treatment in terms of CVS risks in patients with ADHD through its effect on HRV parameters, which are indicators of autonomic system dysfunction. For this purpose, 24-hour rhythm Holter recordings were analyzed in the patients before the drug and one month after they started using the drug, and in the healthy control group. When we compared the patient and healthy control groups before the treatment, SDNN and SDANN, which showed increased sympathetic effect, and rMSSD, which showed decreased parasympathetic effect, were significantly reduced. Again, SDNN, SDANN, and rMSSD times increased in the patient group after the treatment, which showed sympathetic and parasympathetic recovery.

In a similar study, Buchhorn et al.¹⁷ showed that rMSSD was lower in patients compared to healthy controls, supporting the decrease in parasympathetic activity, and that there was an improvement in rMSSD with MPH treatment, but this improvement was more pronounced in night HRV recordings. Similarly, Rukmani et al.⁶ found rMSSD to be lower in the patient group in their study in which they compared the patient and healthy control groups. However, treatment data were not studied. There are studies reporting the opposite result. When Carvalho et al.²⁴ compared the patient and healthy control groups, they found rMSSD to be high in the patient group and interpreted this as an increase in parasympathetic activity. Similar results have been demonstrated in stimulant drug studies. Negrao et al.²¹ found that rMSSD, which shows an increase in parasympathetic activity, increased 3 weeks after drug discontinuation in patients using MPH for ADHD. There are studies that evaluate post-treatment period, such as evaluation after treatment discontinuation. After 12 weeks of MPH treatment, Kim et al.²³ found decreased rMSSD compared to the initial values. Available data are confusing as to whether there is an increase or decrease in vagal tone with disease. The same confusion applies to how vagal healing occurs with treatment. In a recent study by Griffiths et al.²⁶ with a large sample (n=229 patients), although rMSSD was lower in the patient group, there was no significant difference compared to healthy controls, while low rMSSD was associated with high anxiety and social problems. Although low vagal tone has been reported in psychopathological conditions such as depression and anxiety, the relationship between this condition and ADHD appears to be weak if depression, anxiety, and mood disorders are not accompanied²⁷. This may be due to the fact that ADHD is a heterogeneous group with attention deficit, hyperactivity, combined and other psychosocial disorders²⁷. On the other hand, Griffiths et al.²⁶ showed no difference in parasympathetic activity even in ADHD subgroups in the same study. In a study evaluating short-term memory performance, children with ADHD showed excessive vagal withdrawal. If this situation is interpreted together with the study of Buchhorn et al.¹⁷, it can be thought that there may be a daily circadian rhythm in vagal activity. This may also explain why there is a difference in vagal HRV activity at night, while there is no difference in daily measurements²⁸. In a meta-analysis of eight studies (six of which were on children), Koening et al.²⁷ found no evidence of parasympathetic dominance or insufficiency. In our study, rMSSD values were significantly lower in the patient group compared to the healthy controls, suggesting a decrease in parasympathetic activity. At the same time, although rMSSD values did not reach normal healthy control levels after treatment with MPH, they increased and were considered as parasympathetic recovery.

Studies in ADHD are mostly focused on parasympathetic involvement, and the number of studies examining sympathetic involvement is few. Similarly, results regarding whether there is an increase or decrease in sympathetic activity are mixed. Rukmani et al.⁶ found low SDNN values in the patient group in their study in which they compared patients with ADHD and healthy controls, and they evaluated this situation as sympathetic dominance. A similar result was also shown in the study of Carvalho et al.²⁴. The lack of screening of other sympathetic data and inclusion of a small sample were deficiencies for both studies. On the other hand, in the study of Buchhorn et al.¹⁷ in which they compared both before and after treatment with healthy controls, there was no difference in SDNN values. On the contrary, there are studies stating that there is sympathetic insufficiency. Negrao et al.²¹ found both pre- and post-treatment SDNN values higher in patients than in the healthy group and interpreted this as sympathetic insufficiency. A similar result was also found in the study of Kim et al.²⁵, and SDNN decreased with treatment. However, there was no comparison of healthy controls. In our study, SDNN and SDANN values were significantly lower in the patient group compared to the healthy controls, suggesting an increase in sympathetic activity. At the same time, SDNN and SDANN values, which showed sympathetic recovery, increased after treatment with MPH, and this increase was quite close to the healthy control values, especially in SDANN.

Study Limitations

The current study has some limitations. Firstly, it was conducted with a small sample size. Then, the subtypes of the patients were not evaluated, and the HRV was not reviewed again after dose increases during treatment.

TARTIŞMA

DEHB tedavisinde ilk tedavi seçeneği sıklıkla MPH gibi psikostimülan ilaçlardır. Son yıllarda psikostimülan ilaçların olası KVS yan etkileri ile ilgili endişe vardır. Bu konudaki çalışmalar psikostimülan ilaçların KVS üzerine olumlu mu olumsuz mu etkili olduğuyla ilgili oldukça kafa karıştırıcıdır. Çalışmamızda DEHB olan hastalarda MPH tedavisinin KVS riskler açısından potensiyel yarar zarar ilişkisini otonom sistem disfonsiyonunun göstergesi olan HRV parametrelerine etkisi üzerinden araştırmayı amaçladık. Bu amaçla 24 saatlik ritm Holter kayıtları hastalarda ilaç öncesi ve ilaç kullanmaya başladıktan bir ay sonra ve sağlıklı kontrol gurubunda analiz edildi. Tedavi öncesi hasta ve sağlıklı kontrol grubunu karşılaştırdığımızda sempatik etki artışını gösteren SDNN ve SDANN ile parasempatik etki azalışını gösteren rMSSD süreleri belirgin azalmıştı. Yine tedavi sonrası hasta grupta sempatik ve parasempatik iyileşmeyi gösteren SDNN, SDANN ve rMSSD süreleri artış gösterdi.

Buchhorn ve ark.¹⁷ yaptıkları benzer bir çalışmada parasempatik aktivitede azalmayı destekler biçimde hastalarda sağlıklı kontrollere göre rMSSD nin düşük olduğunu ve MPH tedavisi ile hastalarda rMSSD de düzelmenin olduğu ancak bu düzelmenin gece HRV kayıtlarında daha belirgin olduğunu gösterdiler. Benzer biçimde Rukmani ve ark.⁶ hasta ve sağlıklı kontrol grubunu karşılaştırdıkları çalışmalarında hasta grupta rMSSD’yi daha düşük bulmuşlardır. Ancak tedavi verileri çalışılmamıştı. Tam tersi sonuç bildiren çalışmalarda mevcuttur. Carvalho ve ark.²⁴ hasta ve sağlıklı kontrol grubunu karşılaştırdıklarında hasta grupta rMSSD’yi yüksek bulmuşlardır ve bu durumu parasempatik aktivitede artış olarak yorumlamışlardır. Benzer sonuçlar stimulan ilaç çalışmalarında da gösterilmiştir. Negrao ve ark.²¹ DEHB için MPH kullanan hastalarda ilaç kesiminden 3 hafta sonra parasempatik aktivite artışını gösteren rMSSD’nin yükseldiğini bulmuşlardır. Tedavi sonlandırmadan sonra değerlendirme gibi tedavi sonrası değerlendiren çalışmalarda mevcuttur. Kim ve ark.²⁵ 12 haftalık MPH tedavi sonrasında başlangıç rMSSD değerlerine göre düşüş görmüşlerdir. Mevcut veriler hastalıkla vagal tonus artışı mı yoksa azalışı mı olduğu ile ilgili kafa karıştırıcıdır. Aynı karışıklık tedavi ile vagal iyileşmenin ne şekilde olduğu ile ilgili de geçerlidir. Griffiths ve ark.²⁶ yakın zamanlı yaptıkları büyük örneklemli bir çalışmada (n=229 hasta) hasta grupta rMSSD’de daha düşük olmakla birlikte sağlıklı kontrollere göre anlamlı fark yok iken rMSSD’nin düşük olması yüksek kaygı ve sosyal problemlerle ilişkiliydi. Depresyon, anksiyete gibi psikopatolojik durumlarda valgal tonus düşüklüğü bildirilmiş olmakla birlikte bu durumun DEHB ile ilişkisi depresyon, anksiyete, duygu durum bozukluğu eşlik etmiyorsa zayıf gibi gözükmektedir²⁸. Bunun sebebi DEHB nun dikkat eksikliği, hiperaktivite, kombine ve diğer psikososyal bozuklukların olduğu heterojen bir grup olmasından kaynaklı olabilir²⁷. Diğer taraftan Griffiths ve ark.²⁶ aynı çalışmada alt DEHB tiplerinde dahi parasempatik aktivitede fark olmadığını gösterdi. Kısa süreli bellek performansının değerlendirildiği bir çalışmada DEHB olan çocuklarda aşırı valgal geri çekilmenin olduğu görüldü ve bu durum Buchhorn ve ark.¹⁷ çalışması ile birlikte yorumlanacak olursa valgal aktivitede günlük sirkadien bir ritmin söz konusu olabileceği düşünülebilir ve gece ölçümlerinde valgal HRV aktivitesinde farklılık varken günlük ölçümlerde fark olmamasını açıklayabilir²⁸. Koenig ve ark.’nın²⁷sekiz çalışmayı (altısı çocuk) inceledikleri bir meta-analizde parasematik dominans veya yetersizliği gösterir bir kanıt bulunamadı. Çalışmamızda hasta grupta sağlıklı kontrollere göre rMSSD değerleri anlamlı olarak daha düşüktü ve bu durum parasempatik aktivitede azalmayı düşündürmekteydi. Aynı zamanda MPH ile tedavi sonrasında rMSSD değerleri normal sağlıklı kontrol düzeylerine gelmese de yükselme gösterdi ve parasempatik iyileşme olarak değerlendirildi.

DEHB’deki çalışmalar daha çok parasempatik etkilenme üzerine yoğunlaşmış olup sempatik etkilenmeyi irdeleyen çalışma sayısı azdır. Benzer biçimde sempatik aktivitede artmış mı yoksa azalış mı olduğuyla ilgili sonuçlar karışıktır. Rukmani ve ark.⁶ DEHB olan hastalarla sağlıklı kontrolleri karşılaştırdıkları çalışmalarında SDNN değerlerini hasta grupta düşük bulmuşlardır ve bu durumu sempatik baskınlık olarak değerlendirmişlerdir. Benzer bir sonuç Carvalho ve ark.²⁴ çalışmasında da gösterildi. Diğer sempatik verilerin taranmamış olması ve küçük bir örneklem ile çalışılmış olması her iki çalışma için eksiklikti. Diğer taraftan Buchhorn ve ark.¹⁷ hem tedavi öncesi hem de tedavi sonrası ile sağlıklı kontrolleri karşılaştırdıkları çalışmalarında SDNN değerlerinde fark yoktu. Tam tersine sempatik yetersizlik olduğunu söyleyen çalışmalarda mevcuttur. Negrao ve ark.²¹ hastalarda hem tedavi öncesi hem de tedavi sonrası SDNN değerlerini sağlıklı gruba göre daha yüksek bulmuşlardır ve bu durumu sempatik yetersizlik olarak yorumlamışladır. Benzer bir sonuç Kim ve ark.²⁵ çalışmasında da mevcuttu ve tedavi ile SDNN düşüyordu. Ancak sağlıklı kontrol karşılaştırması yoktu. Çalışmamızda hasta grupta sağlıklı kontrollere göre SDNN ve SDANN değerleri anlamlı olarak daha düşüktü ve bu durum sempatik aktivitede artışı düşündürmekteydi. Aynı zamanda MPH ile tedavi sonrasında sempatik iyileşmeyi gösteren SDNN ve SDANN değerleri yükseldi ve bu yükselme özellikle SDANN’de sağlıklı kontrol değerlerine oldukça yaklaştı.

Çalışmanın Kısıtlılıkları

Çalışmamızın kısıtlılıkları, örneklem büyüklüğünün küçük olması, hastaların alt tiplerinin değerlendirilmemiş olması ve tedavi sırasında doz artışlarından sonra HRV’nin tekrar gözden geçirilmemesi olarak sayılabilir.

CONCLUSION

As a result, the use of MPH in ADHD has a positive effect on the autonomic system with a decrease in sympathetic activity and an increase in parasympathetic activity, and it improves CVS functions. In addition, it can be said that HRV is noninvasive, reproducible and useful for possible risk assessment during treatment. Since our study was conducted with a small sample, it cannot be generalized. However, it can be a guide for larger sample studies to be done in the future.

Ethics

Ethics Committee Approval: The study approval was obtained from the ethics committee of Tekirdağ Namık Kemal University non-interventional clinical studies (2021.189.06.19) and was conducted in accordance with the Declaration of Helsinki and Good Clinical Practices (date: 12.11.2020, no: 2020/68).

Informed Consent: Informed consent was obtained from children and their parents.

Peer-review: Externally peer-reviewed.

Authorship Contributions

Concept: Ö.K., S.B., Design: Ö.K., Data Collection or Processing: Ö.K., S.B., Analysis or Interpretation: Ö.K., S.B., Literature Search: Ö.K., S.B., Writing: Ö.K.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.

References

Merikangas KR, He JP, Brody D, Fisher PW, Bourdon K, Koretz DS. Prevalence and treatment of mental disorders among US children in the 2001-2004 NHANES. Pediatrics. 2010;125:75-81.

Visser SN, Danielson ML, Bitsko RH, Holbrook JR, Kogan MD, Ghandour RM, et al. Trends in the parent-report of health care provider-diagnosed and medicated attention-deficit/hyperactivity disorder: United States, 2003-2011. J Am Acad Child Adolesc Psychiatry. 2014;53:34-46.

Polderman TJ, Boomsma DI, Bartels M, Verhulst FC, Huizink AC. A systematic review of prospective studies on attention problems and academic achievement. Acta Psychiatr Scand. 2010;122:271-84.

Tripp G, Wickens JR. Neurobiology of ADHD. Neuropharmacology. 2009;57: 579-89.

Benarroch EE. The central autonomic network: functional organization, dysfunction, and perspective. Mayo Clin Proc. 1993;68:988-1001.

Rukmani MR, Seshadri SP, Thennarasu K, Raju TR, Sathyaprabha TN. Heart Rate Variability in Children with Attention-Deficit/Hyperactivity Disorder: A Pilot Study. Ann Neurosci. 2016;23:81-8.

Pliszka SR, Crismon ML, Hughes CW, Corners CK, Emslie GJ, Jensen PS, et al. The Texas Children’s Medication Algorithm Project: revision of the algorithm for pharmacotherapy of attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2006;45:642-57.

Cilsal E, Yurtcu E, Elatas A. Early Cardiovascular Evaluation after Methylphenidate in Children with Attention-Deficit Hyperactivity Disorder. GMJ. 2020;31:345-8.

Torres-Acosta N, O’Keefe JH, O’Keefe CL, Lavie CJ. Cardiovascular Effects of ADHD Therapies: JACC Review Topic of the Week. J Am Coll Cardiol. 2020;76:858-66.

Visser SN, Danielson ML, Wolraich ML, Fox MH, Grosse SD, Valle LA, et al. Vital Signs: National and State-Specific Patterns of Attention Deficit/Hyperactivity Disorder Treatment Among Insured Children Aged 2-5 Years - United States, 2008-2014. MMWR Morb Mortal Wkly Rep. 2016;65:443-50.

Buchhorn R, Müller C, Willaschek C, Norozi K. How to predict the impact of methylphenidate on cardiovascular risk in children with attention deficit disorder: methylphenidate improves autonomic dysfunction in children with ADHD. ISR Pharmacol. 2012;2012:170935.

Subcommittee on Attention-Deficit/Hyperactivity Disorder; Steering Committee on Quality Improvement and Management; Wolraich M, Brown L, Brown RT, DuPaul G, et al. ADHD: clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Pediatrics. 2011;128:1007-22.

Mick E, McManus DD, Goldberg RJ. Meta-analysis of increased heart rate and blood pressure associated with CNS stimulant treatment of ADHD in adults. Eur Neuropsychopharmacol. 2013;23:534-41.

Nissen SE. ADHD drugs and cardiovascular risk. N Engl J Med. 2006;354: 1445-8.

Winterstein AG, Gerhard T, Kubilis P, Saidi A, Linden S, Crystal S, et al. Cardiovascular safety of central nervous system stimulants in children and adolescents: population based cohort study. BMJ. 2012;345:e4627.

Schelleman H, Bilker WB, Strom BL, Kimmel SE, Newcomb C, Guevara JP, et al. Cardiovascular events and death in children exposed and unexposed to ADHD agents. Pediatrics. 2011;127:1102-10.

Buchhorn R, Conzelmann A, Willaschek C, Störk D, Taurines R, Renner TJ. Herat Rate Variability and Methylphenidate in children with ADHD. Atten Defic Hyperact Disord. 2012;4:85-91.

Thayer JF, Lane RD. A model of neurovisceral integration in emotion regulation and dysregulation. J Affect Disord. 2000;61:201-16.

Thayer JF, Lane RD. The role of vagal function in the risk for cardiovascular disease and mortality. Biol Psychol. 2007;74:224-42.

Tonhajzerova I, Ondrejka I, Adamik P, Hruby R, Javorka M, Trunkvalterova Z, et al. Changes in the cardiac autonomic regulation in children with attention deficit hyperactivity disorder (ADHD). Indian J Med Res. 2009;130:44-50.

Negrao BL, Bipath P, van der Westhuizen D, Viljoen M. Autonomic correlates at rest and during evoked attention in children with attention-deficit/hyperactivity disorder and effects of methylphenidate. Neuropsychobiology 2011;63:82-91.

American Psychiatric Association. Diagnostic and Statistical Manuel of Mental Disorders (5th ed). Arlington, American Psychiatric Publishing, 2013.

M. Malik. Heart rate variability: standards of measurement, physiological interpretation, and clinical use. Circulation. 1996;93:1043-65.

Carvalho TD, Wajnsztejn R, Abreu LC, Vanderlei LCM, Godoy MF, Adami F, et al. Analysis of cardiac autonomic modulation of children with attention deficit hyperactivity disorder. Neuropsychiatr Dis Treat. 2014;10: 613-8.

Kim HJ, Yang J, Lee MS. Changes of Heart Rate Variability during Methylphenidate Treatment in Attention-Deficit Hyperactivity Disorder Children: A 12-Week Prospective Study. Yonsei Med J. 2015;56:1365-71.

Griffiths KR, Quintana DS, Hermens DF, Spooner C, Tsang TW, Clarke S, et al. Sustained attention and heart rate variability in children and adolescents with ADHD. Biological Psychol. 2017;124:11-20.

Koenig J, Rash JA, Kemp AH, Buchhorn R, Thayer JF, Kaess M. Resting state vagal tone in attention deficit (hyperactivity) disorder: A meta-analysis. World J Biol Psychiatry. 2017;4:256-67.

Ward AR, Alarcon G, Nigg JT, Musser ED. Variation in parasympathetic dysregulation moderates short-term memory problems in childhood attention-deficit/hyperactivity disorder. J Abnorm Child Psychol. 2015;43:1573-83.