10.24265/horizmed.2024.v24n2.14

Review Article

Cardiovascular risk and pharmacotherapy in pediatric patients with attention-deficit hyperactivity disorder

Daniel Aicardo Ortega Delgado ¹0000-0003-3918-9093

Angelie Charlotte Sánchez Solarte ^2,0009-0000-1137-3652

Mónica Tatiana Leguizamón Sotto ^3, 0009-0007-7607-040X

Erika Alejandra Rodríguez Velásquez ^3, 0009-0008-1116-5595

Geraldine Rodríguez Quiroga ^4,0009-0004-3614-2550

Astrid Natalia Hurtado Cerón ^5, 0000-0001-6091-7345

María Carolina Peña Hernández ^6,0009-0001-5409-0780

María Paz Bolaño Romero ^7, 0000-0001-8962-6947

¹.Universidad Libre, Departamento de Psiquiatría (Department of Psychiatry). Cali, Colombia.

².Universidad de Antioquia, Departamento de Pediatría (Department of Pediatrics). Medellín, Colombia.

³.Fundación Universitaria Juan N. Corpas, Departamento de Medicina (Department of Medicine). Bogotá, Colombia.

⁴.Corporación Universitaria Rafael Núñez, School of Medicine. Cartagena, Colombia.

⁵.Universidad ICESI, School of Medicine. Cali, Colombia.

⁶.Universidad del Sinú, School of Medicine. Cartagena, Colombia.

⁷.Universidad de Cartagena, School of Medicine. Cartagena, Colombia.

a. Psychiatry resident

b. Pediatrics resident

c. General practitioner

^*Corresponding author.

ABSTRACT

Mental health is one of the current pillars of global health; therefore, it is considered an essential factor in the well- being and quality of human life. The dramatic growth in the incidence and prevalence of mental disorders has brought about a burden of silent and unsustainable disease for healthcare systems, especially in younger age groups such as children and adolescents. Although major depressive disorder, anxious syndrome, and conduct and eating disorders are some of the most frequent in this age group, attention-deficit hyperactivity disorder (ADHD) is also an entity of interest affecting between 5 % and 10 % of children. There exists a pharmacological treatment for this condition, and it is based on stimulant and non-stimulant medications. Evidence of the highest quality has recently demonstrated that children and adolescents who were administered ADHD medications had a higher risk of some cardiovascular event compared to those who were not. Considering the impact and relevance of ADHD in the child and adolescent populations at present, as well as the use of drugs for its control, it is imperative to have evidence of the highest quality for decision-making in clinical practice. To date, there is no evidence in Spanish that has synthesized and analyzed this phenomenon. Based on the foregoing, the objective of this review is to analyze the most recent evidence of the association between cardiovascular risk and pharmacotherapy in pediatric patients with ADHD. A literature search was conducted using the search terms "Cardiovascular Risk," "Attention Deficit Hyperactivity Disorder," and "Pediatric," in addition to synonyms, which were combined with the operators "AND" and "OR," in the PubMed, ScienceDirect, Web of Science, and MEDLINE databases. After reviewing the most recent literature, it was identified that the quality of the current evidence regarding the association between increased cardiovascular risk secondary to pharmacotherapy in children and adolescents with ADHD is very low, heterogeneous, and fragmented. Nevertheless, the trend suggests that there may be a potential risk of the alteration of hemodynamic parameters, essentially heart rate and blood pressure, without involving the frequent or significant occurrence of serious cardiovascular adverse events. However, the evidence suggests continuous monitoring.

Keywords: Heart Disease Risk Factors; Drug Therapy; Attention Deficit Disorder with Hyperactivity; Child; Adolescent (Source: MeSH NLM).

INTRODUCTION

Mental health is one of the current pillars of global health and is considered an essential factor in the well-being and quality of human life ⁽¹⁾. The dramatic growth in the incidence and prevalence of mental disorders has brought about a burden of silent and unsustainable disease for healthcare systems, especially in younger age groups- such as children and adolescents-where neuropsychiatric manifestations and fatal outcomes are increasingly frequent ⁽²⁾. An alarming transition of the burden of disease specifically among children and adolescents under 20 years of age has been described, reporting 21.5 million disability-adjusted life years (DALYs) by 2019 ⁽³^,⁴⁾. It is also estimated that this number will increase due to current environmental exposure and lifestyle ⁽⁵⁾. Although major depressive, anxiety and eating disorders are some of the most common, attention-deficit hyperactivity disorder (ADHD) is also a condition of interest affecting 5 %-10 % of children and impacting the health outcomes of those affected ⁽⁶⁾.

ADHD is defined as a psychiatric disorder that compromises the functionality of affected individuals, due to a pattern characterized by inadequate levels of concentration, hyperactivity or impulsivity ⁽⁷^-⁹⁾. It is more common in children and adolescents, initially presenting with disorganization and inattentiveness at school age and during their development ⁽¹⁰^,¹¹⁾. However, these manifestations lead to the category of a disorder only when they disrupt activities of daily living. To date, there are several treatments that have proven to be effective in controlling them, but they are not entirely safe ⁽⁸^,⁹⁾. Considering that the two available pharmacological groups are stimulants and non-stimulants, the side effects and adverse events range from hemodynamic and endocrine cycle alterations to the risk of dependence ⁽⁷^,¹²^,¹³⁾. It has been previously described that these side effects and/or adverse events can have a significant influence on the quality of life of affected individuals. Although, there is another highly relevant adverse event: the cardiovascular risk associated with the use of ADHD medications ⁽¹⁴^-¹⁸⁾.

Recent evidence of the highest quality demonstrated that children and adolescents who were administered ADHD medications had a higher risk of experiencing a cardiovascular event, compared to those who were not ⁽¹⁸⁾. Considering the impact and relevance of ADHD in child and adolescent populations today, as well as the use of drugs to control it, it is crucial to have the best quality evidence for decision-making in healthcare practice, particularly in Spanish. Based on the foregoing, the objective of this review is to analyze the most recent evidence on the association between cardiovascular risk and pharmacotherapy in pediatric patients with ADHD.

SEARCH STRATEGY

A literature search was conducted using the search terms “Cardiovascular Risk,” “Attention Deficit Hyperactivity Disorder” and “Pediatric,” as well as synonyms, which were combined with the operators “AND” and “OR” in the PubMed, ScienceDirect, Web of Science and MEDLINE databases. We included all available full-text articles that evaluated the association between pharmacotherapy in pediatric patients with ADHD and cardiovascular risk, prioritizing original studies, systematic reviews and meta-analyses. Articles published up to the year 2023 were included. A total of 94 potentially relevant articles were identified, with a review of their titles and abstracts, of which 61 were finally included. The estimates and calculations found were presented in their original measures, whether as frequencies, percentages, confidence intervals (CI), mean difference (MD), relative risk (RR), odds ratio (OR) or hazard ratio (HR).

Effects of psychiatric medications on the cardiovascular system

To date, several mechanisms have been described that may be related to the instability of metabolic regulation and may have a direct influence on cardiovascular health ⁽¹⁹^-²²⁾. Initially, it has been mentioned that many of these psychiatric drugs antagonize both H₁ and α₁-adrenergic and serotonergic receptors, which are related to appetite centers, thus resulting in increased food intake and weight gain ⁽¹⁹⁾. This would explain why greater weight gain occurs with monoamine oxidase inhibitors and tricyclic antidepressants, which generate potent H₁ receptor antagonism. Additionally, these drugs interact with the regulation of leptin and adiponectin ⁽²⁰⁾. For example, lithium inhibits the enzyme glycogen synthase kinase-3 beta, and blocks the ability of leptin to reduce caloric intake, leading to weight gain. The use of sodium valproate has been found to have a dose-dependent inhibitory effect on the expression of adiponectin, which is a hormone that regulates glucose homeostasis and insulin sensitivity ⁽²¹^,²²⁾. For this reason, its use could trigger an obesogenic and insulin-resistant process.

Other mechanisms are linked to dyslipidemia, as many of these drugs interact at the level of enzymes and lipid pathways related to the synthesis and degradation of these compounds ⁽¹⁹⁾. Haloperidol, a typical antipsychotic, inhibits the cholesterol biosynthesis reaction catalyzed by reductases and isomerases. Clozapine and risperidone, atypical antipsychotics, also inhibit reductases and isomerases involved in this signaling pathway. Therefore, they have the potential to alter lipid metabolism by accumulating sterol intermediates and to cause dyslipidemia ⁽²³^,²⁴⁾. Another pharmacological group linked to this process is that of antidepressants, whose mechanism of action is related to the activation of sterol regulatory element binding protein (SREBP) transcription factors, involved in the biosynthesis of cholesterol and fatty acids ⁽²⁵^,²⁶⁾.

An additional mechanism is insulin resistance, induced by several pharmacological groups such as second-generation antipsychotics, some of which increase serum glucose levels in a dose-dependent manner, as some of these molecules activate adenosine monophosphate (AMP)-dependent kinases in the hypothalamus, generating a gluconeogenic drive through the sympathetic nervous system ⁽¹⁹^,²⁷⁾. This has been demonstrated by studies in biological models, in which an inhibitor of the aforementioned kinase was administered after these drugs, resulting in a reduction in hyperglycemia ⁽²⁸^-³⁰⁾. It is even presumed that there are unclear epigenetic mechanisms that may cause this hyperglycemic effect by impairing timely response to glucose homeostasis ⁽¹⁹⁾.

Finally, but not less importantly, psychotropic drugs with serotonergic 5HT2A antagonist activity cause vascular contraction, increasing peripheral vascular resistance and, consequently, blood pressure ⁽³¹⁾. Some drugs that interact with α₁-adrenergic receptors also cause an increase in blood pressure levels through the same mechanism. Likewise, due to their anticholinergic effect, tricyclic antidepressants also contribute to increase blood pressure ⁽³²^-³⁴⁾. Psychostimulants, by releasing norepinephrine, dopamine and serotonin, have a positive effect on central dopaminergic and peripheral adrenergic centers, which influence this same hemodynamic parameter ⁽³³^,³⁴⁾.

Thus, these factors, added to an unhealthy lifestyle, genetic load and environmental exposure, can undoubtedly trigger significant cardiometabolic damage which, in theory, could increase the cardiovascular risk of those who aggressively and continuously take certain psychiatric drugs (Figure 1). Therefore, risk analysis and assessment should be conducted on an individualized basis.

Figure 1. Mechanisms associated with hemodynamic, electrophysiological and cardiometabolic alterations in children and adolescents with ADHD and the administration of stimulant or non-stimulant psychotropics

Does the evidence support an increased cardiovascular risk secondary to ADHD medication among pediatric patients?

To date, the evidence concerning cardiovascular risk in children and adolescents receiving ADHD medication is scarce and exhibits varying degrees of fragmentation as to external validity. This is predominantly due to the fact that much of the evidence comes almost exclusively from high- income countries where outcome assessments differ.

One of the most recent studies was conducted by Huber et al. ⁽³⁵⁾, who evaluated the change in serum lipoprotein levels in children and adolescents with ADHD receiving treatment, with a 10-year follow-up, in Germany. Methylphenidate was one of the most frequently identified drugs in this cohort. The researchers observed no baseline differences at the start of the analysis between the exposed group (n = 1,219) and the control group (n = 9,741) for cholesterol (p = 0.979), triglycerides (p = 0.412), low-density lipoproteins (LDL) (p = 0.525) and high- density lipoproteins (HDL) (p = 0.366). Interestingly, no changes were evident during the follow-up period, even in cases where methylphenidate was used. Therefore, the authors concluded that there was no association between ADHD medication, or the diagnosis itself, with alterations in lipid parameters suggesting any type of cardiovascular disorder ⁽³⁵⁾. Nevertheless, some years ago, Martinez-Raga et al. ⁽³⁶⁾ suggested serious risks of vascular problems associated with this type of medication, specifically with stimulants such as methylphenidate and amphetamine derivatives, which had been shown to increase heart rate and blood pressure. In contrast, drugs such as clonidine or guanfacine, whether administered alone or in combination with other psychostimulants, have been shown to cause a decrease in these hemodynamic parameters without altering cardiac electrophysiology. However, by that time, it seemed that atomoxetine and α₂- adrenergic agonists presented a better benefit-risk balance as the risk of serious cardiovascular adverse events was extremely low ⁽³⁶⁾.

Man et al. ⁽³⁷⁾ published the most recent primary study (Attention Deficit Hyperactivity Disorder Drugs Use Chronic Effects - ADDUCE study; as of 2023), which explored the long-term outcomes of using methylphenidate in children and adolescents with ADHD and its association with chronic effects. This longitudinal controlled study was conducted in 27 specialized centers located across Germany, the United Kingdom, Italy, Switzerland and Hungary, including 1,410 individuals (756 in the methylphenidate group,

391 in the non-methylphenidate group and 263 in the control group) with average age of approximately nine years. During the 24 months of treatment and follow-up, the methylphenidate group did not show any difference compared to the non-methylphenidate group (p = 0.20) regarding the increased risk of adverse events. In spite of the fact that hemodynamic parameters such as heart rate and blood pressure were higher in the methylphenidate group, this was not associated with any relevant cardiovascular adverse events. Hence, the authors concluded that the use of this drug to treat ADHD in children and adolescents is safe, but continuous monitoring of hemodynamics should not be omitted ⁽³⁷⁾.

Despite the uncertainty, existing systematic reviews and meta-analyses have only analyzed these events as secondary outcomes in nonspecific studies. A Cochrane Review published in 2018 ⁽³⁸⁾, which included adverse events studied in non-randomized research conducted among children, adolescents and young adults (aged 3 to 20 years) with ADHD treated with methylphenidate, indicated, first, that the quality of the evidence found was very low, and, second, that methylphenidate increased by up to 36 % the risk of any serious adverse event (95 % CI: 1.17-1.57) related to psychotic disorder (95 % CI: 1.17- 1.57), and up to 61 % the risk of arrhythmia (95 % CI: 1.48- 1.74), compared to the control group. Additionally, the use of this drug was reported to increase sleep problems by 158 % (95 % CI: 1.24-5.34) and raise the risk of decreased appetite 15 times (95 % CI: 2.12-106.83) ⁽³⁸⁾. Up to this point in time, it was suggested-based on limited rationale-that methylphenidate might be associated with a significant number of serious and nonserious adverse events. As of 2023, this same review was updated ⁽³⁹⁾, this time including more than 30,000 individuals with a mean age of 10 years and average treatment duration with methylphenidate of 29 days. Unlike the previous review, this one found that methylphenidate did not modify the risk of serious adverse events (RR 0.80; 95 % CI: 0.39-1.67), although this estimate obtained a very low certainty. Similarly, regarding whether it could cause nonserious adverse events compared to placebo or no intervention (RR 1.23; 95 % CI 1.11-1.37), the certainty was also very low ⁽³⁴⁾. Thus, these reviews have been inconclusive and imprecise due to the low quality of the evidence.

Slightly different from the previous approach, Cerrillo- Urbina et al. ⁽³⁹⁾ conducted a meta-analysis of randomized controlled trials that assessed the safety and efficacy of stimulant and non-stimulant drugs among children and adolescents with ADHD, including 15 trials with a total of 4,648 individuals aged 6 to 17 years. Although both pharmacological groups were found to be effective for symptom control, the most frequent adverse events in the stimulant and non-stimulant groups were decreased appetite (28.6 % vs. 14.2 %) and altered sleep quality (4.4 % vs. 34.1 %), respectively ⁽³⁹⁾.

The remaining available evidence from qualitative reviews differs in approach, showing inconclusive results and numerous hypotheses without solid support, whether from basic, clinical or translational research (⁴⁰-⁴⁴). Zhang et al. ⁽¹⁸⁾ may be the authors with the most robust and transparent evidence to date concerning the cardiovascular risk from ADHD medication. Despite this analysis comprised children, adolescents, and adults (more than 3 million individuals drawn from 19 studies), it had a median follow-up of 1.5 years. The overall analysis demonstrated that there was no association between the use of any medication with cardiovascular disease in children or adolescents (RR 1.18; 95 % CI 0.91-1.5), or adults (RR 1.04; 95 % CI 0.43-2.48).

When analyzed by pharmacological group, no association was found for stimulants (RR 1.24; 95 % CI 0.84-1.83) or non-stimulants (RR 1.22; 95 % CI 0.25-5.97). Likewise, when analyzing by cardiovascular condition, such as, e.g., arrhythmia or cardiac arrest (RR 1.60; 95 % CI 0.94-2.72), cerebrovascular disease (RR 0.91; 95 % CI 0.72-1.1) or

acute myocardial infarction (RR 1.06; 95 % CI 0.68-1.65), no associations were found. This allowed the researchers to conclude that there is no association between the use of ADHD drugs and increased cardiovascular risk ⁽¹⁸⁾. However, it should be noted that the follow-up period was quite short. Therefore, the evidence to answer this research question remains weak and very heterogeneous.

Future perspectives

In view of the dramatic transition with a growing trend in the prevalence and incidence of mental disorders-such as ADHD-particularly in children and adolescents, various authors have proposed relevant and consistent lines of study in accordance with global health needs ⁽⁴⁵^-⁴⁹⁾. The safety and efficacy of novel molecules, as well as the pluralism and identification of ADHD phenotypes, particularly in preschool children, are essential for the early approach, preventing the condition from progressing to severe manifestations and affecting the neurodevelopment of children or adolescents ⁽⁵⁰⁾. Priority should be given to translational research aimed at gaining a deeper understanding of new phenotypes or clustered phenotypes, as well as the search for biomarkers and new signaling pathways to identify increasingly precise therapeutic targets ⁽⁵¹^-⁵⁴⁾. This type of research should be encouraged with funding support from the government, private enterprises and higher education institutions, which should also provide comprehensive training for healthcare professionals. This training should emphasize mental disorders, enabling them to rigorously and precisely address the burden of disease that is faced in silence.

At present, multidomain computerized models based on neuroimaging studies are being developed to help understand the affected brain areas ⁽⁵⁵^-⁵⁷⁾ in order to facilitate the approach to pharmacological, occupational, psychiatric and psychological therapies. This is the perfect time to study these conditions in developing countries, where there is a significant evidence gap, as well as a lack of highly specialized centers for widespread treatment of patients with ADHD. In addition, such centers would serve as sites for conducting randomized controlled trials to evaluate the safety, efficacy and efficiency of ADHD drugs (⁵⁹-⁶⁴) and their association with long-term cardiovascular, neurological and psychiatric outcomes, taking into account the health context of each region ⁽⁶⁵⁾. Timely and specialized access to mental healthcare is a dilemma faced by health systems ⁽⁶⁶^,⁶⁷⁾, for which upcoming development plans and health strategies should align with the needs expressed by international organizations and scientific societies, in order to act at the local and national levels but with the potential to contribute to the scientific evidence at the international level ⁽⁶⁸^,⁶⁹⁾.

CONCLUSIONS

Although the quality of the current evidence regarding the association between increased cardiovascular risk secondary to pharmacotherapy in children and adolescents with ADHD is very low, heterogeneous and fragmented, the trend suggests that there may be a potential risk in the alteration of hemodynamic parameters, essentially heart rate and blood pressure, without involving the frequent or significant occurrence of serious adverse cardiovascular events. However, the evidence suggests the need for continuous monitoring.

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Author contributions: DAOD, ACSS and MTLS have similarly contributed to the original idea, study design, literature collection and analysis, writing the draft and the article, and approval of the final version. EARV, GRQ, ANHC, MCPH and MPBR have participated in the conception and design of the article, analysis and interpretation of data, writing the article, critical review of the article and approval of the final version.

Funding sources: This article was funded by the authors.

Conflicts of interest: The authors declare no conflicts of interest.

^*Corresponding author:

María Paz Bolaño Romero

Address: Grupo Prometheus y Biomedicina Aplicada a las Ciencias Clínicas, Facultad de Medicina, Universidad de Cartagena, Cartagena, Colombia

Telephone: +57 321 554 2500

E-mail: mbolanor1@unicartagena.edu.co

Reception date: December 4, 2023

Evaluation date: December 10, 2023

Approval date: December 18, 2023