Risk of Serious Cardiovascular Problems with Medications for Attention-Deficit Hyperactivity Disorder

Abstract

Attention-deficit hyperactivity disorder (ADHD) is a chronic neurodevelopmental disorder characterized by persistent symptoms of inattention, hyperactivity and/or impulsivity. The proportion of patients diagnosed with ADHD receiving pharmacological treatments has increased enormously in recent years. Despite the well established efficacy and the good safety and tolerability profile, there is concern about the potential for rare but serious cardiovascular adverse events, as well as sudden cardiac death, with pharmacotherapies used for treating ADHD in children, adolescents and adults. The present paper aims to comprehensively and critically review the published evidence on the controversial association between medications approved for treating patients with ADHD and the risk of serious cardiovascular problems, specifically the risk of corrected QT interval (QTc) prolongation, and the risk of sudden cardiac death. A comprehensive search of relevant databases (PubMed, EMBASE and PsychINFO) was conducted to identify studies published in peer-reviewed journals until 21 July 2012. Clinical reports, as well as retrospective or prospective population-based studies with children, adolescents or adults as participants, of pharmacotherapies for ADHD reporting cardiovascular adverse events were included. Stimulant medications for ADHD, including methylphenidate and amphetamine derivatives, are generally safe and well tolerated. Small but statistically significant increases in blood pressure (BP) and heart rate (HR) are among the adverse events of stimulant treatment in all age groups. Similarly, the non-stimulant medication atomoxetine has also been associated with increased HR and BP, although as is the case with stimulants, these are generally minor, time limited and of minor clinical significance in children, adolescents or adults. Growing evidence suggests that these medications do not cause sudden and unexpected cardiac death or serious cardiovascular problems including statistically or clinically significant increases in QTc, at therapeutic doses in ADHD patients across the lifespan. Small decreases in mean systolic BP, diastolic BP and HR have been observed in studies with guanfacine-extended release (-XR) or clonidine-XR, two α(2)-adrenergic receptor agonists, administered alone or in combination with psychostimulants to children and adolescents with ADHD. There are also no statistically or clinically significant increases in QTc associated with clonidine or guanfacine. There are no reports of torsades de pointes clearly and directly related to medications used for treating ADHD in patients of all age groups. The risk for serious cardiovascular adverse events, including statistically or clinically significant increases in QTc, and sudden cardiac death associated with stimulants, atomoxetine or α(2)-adrenergic agonists prescribed for ADHD is extremely low and the benefits of treating individual patients with ADHD, after an adequate assessment, outweigh the risks. However, great caution is advised when considering stim...

A Review of Pharmacological Management of Attention-Deficit/Hyperactivity Disorder

“…33 Atomoxetine is relatively well tolerated by patients. 34 Somnolence, dry mouth, nausea, constipation, dizziness, and decreased appetite are often seen early in the treatment course and tend to subside significantly over time. 29 Insomnia may develop over time and may be worse in those patients with evening doses.…”

“…Immediate-release clonidine and guanfacine, alpha 2 -agonists used for blood pressure control, were used off-label as second-line agents for patients failing 2 psychostimulants or as adjunctive therapy for patients with suboptimal results with a psychostimulant alone. 1,33,34 These agents were also used if the patient had a comorbid condition resulting in tics, such as Tourette's disorder, which could be exacerbated by psychostimulant therapy. 35 However, these agents could be difficult for the patient to tolerate owing to their side effect profile and they may place the patient at a significant risk for rebound hypertension if abruptly discontinued.…”

“…Recently, extendedrelease versions of each drug have become available, which minimize the initial drop in blood pressure and are better tolerated than their immediate-release counterparts. 34 These agents should be considered for patients that have failed psychostimulant monotherapy or atomoxetine or require treatment for comorbid psychiatric conditions. Additionally, patients exhibiting aggression may benefit from alpha 2 -agonist therapy owing to its subtle sedative effect.…”

“…42,43 The exact mechanism of action for the alpha 2 -agonists in ADHD is not known. 34 The predominant theory is that these agents work by directly mimicking norepinephrine effects at the alpha 2A adrenoreceptors in the prefrontal cortex. Guanfacine is selective for the alpha 2A adrenoreceptors, while clonidine is active at the alpha 2A,B, and C adrenoreceptors.…”

“…Theoretically, this implies that guanfacine and clonidine will have similar efficacy via stimulation of the alpha 2A adrenoreceptors, but guanfacine may have less sedation and impact on blood pressure owing to its lack of effect on the alpha 2B and C adrenoreceptors. 34 Each product has its own unique dosing regimen. Extended-release guanfacine, Intuniv (Shire US), is approved for patients older than 6 years and is initiated at a dose of 1 mg per day.…”