Stimulants and Sudden Death: What Is a Physician to Do?

Clinical Research Program in Pediatric Psychopharmacology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
PEDIATRICS (Impact Factor: 5.47). 10/2006; 118(3):1215-9. DOI: 10.1542/peds.2006-0942
Source: PubMed


Recently, a US Food and Drug Administration advisory committee raised concerns about cardiovascular risks and sudden death in children and adolescents with attention-deficit/hyperactivity disorder who are receiving stimulants.
We comment on the risk of sudden death in children/adolescents taking stimulants compared with population rates, biological plausibility, and known cardiovascular effects of stimulants to determine specific risk.
There does not seem to be higher risk of sudden death in stimulant-treated individuals compared with the general population. Although there is evidence of biological plausibility, the known effects of the stimulants on cardiovascular electrophysiology and vital signs seem to be benign.
There does not seem to be compelling findings of a medication-specific risk necessitating changes in our stimulant treatment of children and adolescents with attention-deficit/hyperactivity disorder. The use of existing guidelines on the use of stimulants (and psychotropic agents) may identify children, adolescents, and adults who are vulnerable to sudden death.

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    • "However, the methodology of this study has come in for some criticism. Data from the WHO for the period 1999–2003 report the occurrence of 25 sudden deaths under psychostimulants , of which 8 were with methylphenidate (7 children, 1 adult) (Wilens et al. 2006). On 1 November 2011, the FDA published a statement for the general public emphasizing the absence of any relation between the use of psychostimulant drugs for the treatment of ADHD, and the appearance of adverse cardiovascular effects. "
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    ABSTRACT: Methylphenidate is a piperidine derivative structurally and pharmacologically similar to amphetamine. Methylphenidate is indicated for Attention Deficit Hyperactivity Disorder (ADHD) in children aged 6 years of age and over when remedial measures alone prove insufficient. In adults, its indication, except in narcolepsy, is not defined. Methylphenidate received regulatory approval almost sixty years ago with a first registration in Switzerland in October 1954. To evaluate the off-label use of methylphenidate and its characteristics from a database of spontaneous reports. This study analysed data from the French Pharmacovigilance Database of adverse drug reactions spontaneously reported by health professionals from 1985 to December 2011. Off-label use was evaluated according to age. In the French Pharmacovigilance database, 181 cases of adverse drug reactions were reported with methylphenidate. Neuropsychiatric effects were the most frequent adverse event reported (41%) followed by cardiovascular and cutaneous side effects (14%). 143 reports concerned children (113 boys, 30 girls, mean age 10.6 ± 3.3 years) of which 46 (30%) were off-label uses. There were 38 adults (20 men, 18 women), of which 32 (88%) off-label use. In adults, methylphenidate was prescribed for depression, and this practice was associated with serious adverse events of drug dependence, overdose and suicide attempt. Overall, off-label use was detected in 43% (78/181) of all cases reported. More than 40% of the patients with drug reactions received methylphenidate for off-label indications. Additional long-term exposures and independent clinical studies are necessary to establish the long-term profile safety of methylphenidate.
    Full-text · Article · Jun 2014 · SpringerPlus
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    • "Unfortunately, the majority of patients with structural cardiac abnormalities are asymptomatic and therefore unable to be diagnosed, and SUD is often the first indication of these heart problems (Wilens et al. 2006). Moreover , Wilens et al. noted that there are no current medical procedures to detect structural cardiac abnormalities prior to autopsy. "
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    ABSTRACT: To alert professionals and consumers about safety risks associated with approved drugs, the U.S. Food and Drug Administration (FDA) periodically issues Drug Safety Communications, or DSCs (previously known as advisories, warnings, and health care professional letters). This review consolidates balanced information from 22 DSCs issued over the last 15 years by the FDA for drugs with pediatric indications (for any disorder) that are used to treat pediatric emotional and behavioral disorders (ADHD drugs, antipsychotics, antidepressants, and antiepileptics/anticonvulsants). A single-source document of pediatric DSCs for these drugs was needed because none existed previously; finding DSC information on the FDA website can be challenging; and other information sources (e.g., manufacturer or advocacy websites, blogs, other media reports) may lack the objectivity or accuracy that the FDA is charged to maintain. This consolidation is intended to enable better informed risk-benefit analysis around treatment selection and drug safety monitoring. For the 22 DSCs, we summarize the safety concerns, the populations affected, and when available from the FDA, the incidence of the adverse events, precursors, and factors that may increase or mitigate the risk of these very serious (e.g., sudden death, life-threatening rash, liver failure), but typically low incidence (<1 %) adverse events (cardiometabolic complications with atypical antipsychotics and suicidality with antidepressants are more common). This review does not address the far more common, but usually less serious, side effects that also accompany these drugs. Implications of this review for research and practice are discussed.
    Full-text · Article · May 2014 · Journal of Child and Family Studies
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    • "Cardiovascular safety concerns with psychostimulant ADHD medications were raised based on rare occurrences of sudden death and other cardiac events (Vetter et al. 2008). Psychostimulants modulate cardiovascular contractility and heart rate via sympathomimetic effects (Wilens et al. 2006b), and changes in vital signs have been noted with MPH and AMP treatments, including increases in systolic and diastolic blood pressure (~2–6 mmHg) and heart rate (~8 beats per minute) (Wilens et al. 2005). In clinical trials of psychostimulants in children and adults, no clinically significant changes in atrial or ventricular conduction or repolarization have been observed (Wilens et al. 2006b). "
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    ABSTRACT: Individuals with attention-deficit/hyperactivity disorder (ADHD) show pervasive impairments across family, peer, and school or work functioning that may extend throughout the day. Psychostimulants are highly effective medications for the treatment of ADHD, and the development of long-acting stimulant formulations has greatly expanded the treatment options for individuals with ADHD. Strategies for the formulation of long-acting stimulants include the combination of immediate-release and delayed-release beads, and an osmotic-release oral system. A recent development is the availability of the first prodrug stimulant, lisdexamfetamine dimesylate (LDX). LDX itself is inactive but is cleaved enzymatically, primarily in the bloodstream, to release d-amphetamine (d-AMP). Several clinical trials have demonstrated that long-acting stimulants are effective in reducing ADHD symptoms compared with placebo. Analog classroom and simulated adult workplace environment studies have shown that long-acting stimulants produce symptom reduction for at least 12 h. Long-acting stimulants exhibit similar tolerability and safety profiles to short-acting equivalents. While variations in gastric pH and motility can alter the availability and absorption of stimulants released from long-acting formulations, the systemic exposure to d-AMP following LDX administration is unlikely to be affected by gastrointestinal conditions. Long-acting formulations may also improve adherence and lower abuse potential compared with their short-acting counterparts. The development of long-acting stimulants provides physicians with an increased range of medication options to help tailor treatment for individuals with ADHD.
    Full-text · Article · Apr 2013 · ADHD Attention Deficit and Hyperactivity Disorders
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