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Our reference: JAC 27476 P-authorquery-v9
AUTHOR QUERY FORM
Journal: JAC
Article Number: 27476
Please e-mail your responses and any corrections to:
T he most commonly diagnosed and pharma-cologically treated behavioral disorder inchildren and adolescents is attention-
deficit/hyperactivity disorder (ADHD). Stimulantshave been shown to significantly improve the ADHDsymptoms, physical hyperactivity and inability tosustain mental focus, in children and adults (1–3).All ADHD medications have warnings on their pack-age inserts regarding potential serious adverse car-diovascular (CV) reactions and blood pressure (BP)elevations (4). Currently, 6.1 million U.S. childrenand adolescents are taking U.S. Food and DrugAdministration (FDA)-approved ADHD medications,which include amphetamine salts (Adderall), methyl-phenidate (Ritalin), lisdexamfetamine (Vyvanse),atomoxetine (Strattera), and methamphetamine (Des-oxyn) (5).
N 0735-1097/$36.00
m the aUniversity of Missouri-Kansas City, Kansas City, Missouri; bSain
ssouri; cTulane University, New Orleans, Louisiana; and the dJohn Och
ool-University of Queensland School of Medicine, New Orleans, Louisia
rdioTabs. All other authors have reported that they have no relationships
e authors attest they are in compliance with human studies committe
titutions and Food and Drug Administration guidelines, including patien
it the JACC author instructions page.
nuscript received December 4, 2019; revised manuscript received May 21
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All drugs used to treat ADHD are sympathomi-metic amines with similar chemical structures andphysiological activities. These compounds exertstimulant effects on the central nervous system byincreasing the levels of noradrenaline and dopa-mine levels in the prefrontal cortex and stimulateadrenergic receptors in the heart and blood vesselsleading to small increases in resting heart rate(RHR) and BP (6).
RISING PRESCRIPTIONS FOR ADHD DRUGS
The availability and use of sympathomimetic aminesto treat ADHD have expanded in recent years; forexample, there was a 3-fold increase in worldwideproduction of methylphenidate between 2000 and2010 (7).
https://doi.org/10.1016/j.jacc.2020.05.081
Q2t Luke’s Mid America Heart Institute, Kansas City,
sner Heart and Vascular Institute, Ochsner Clinical
na. Dr. O’Keefe has a major ownership interest in
relevant to the contents of this paper to disclose.
es and animal welfare regulations of the authors’
t consent where appropriate. For more information,
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HIGHLIGHTS
� Use of prescription sympathomimeticdrugs for treating ADHD has markedlyincreased in the United states.
Presently, 5.2% of all U.S. children 2 to 17years of age are using ADHD prescriptions (5).Although the global prevalence of ADHD hasremained stable over the past 3 decades (8),the diagnosis of ADHD increased by 26% inU.S. children 5 to 11 years of age from 2007 to2016, while the diagnosis in U.S. adultsincreased by 123% during the same period(9). ADHD medication prescriptions filled byadult females increased by 344% between2003 and 2015 (10). This is of particularconcern because adults w50 years of ageappear to be more vulnerable to adverse CVeffects of ADHD drugs than children (11–14),presumably because of the greater risk ofunderlying CV disease.
The American Academy of Pediatrics recommendsthat behavioral (nondrug) therapy should be the firstline of treatment before ADHD medications (8).However, among U.S. children with diagnoses ofADHD, 77% were currently taking prescription sym-pathomimetic amines, whereas 47% had receivedbehavioral therapy in the preceding 12 months (5).Similar findings have been published by the U.S.Centers for Disease Control and Prevention, showing75% of the children with ADHD diagnoses weretreated with stimulants, whereas psychological ser-vices were provided to approximately 50% of ADHDchildren (15). The percentage of children taking ADHDmedications has been increasing in the United Statesand Canada and is now approximately 5- to 10-foldhigher in North America than in other developed na-tions in Europe and Asia (Figure 1) (16). The reasonsfor this are speculative but could include greater fa-miliarity with ADHD medications among practitionersin North America; cost and availability barriers toimplementing behavioral therapy; and/or indirecteffects of educational reform laws in which schoolpersonnel recommend that parents with lowacademically performing children be evaluated forADHD (17).
AUTONOMIC NERVOUS SYSTEM AND
CV HEALTH
Chronic excessive sympathetic nervous system (SNS)activity increases the cardiac workload and pre-disposes to hypertension, endothelial dysfunction,left ventricular hypertrophy, and episodes ofarrhythmia, whereas increased vagal activity vaso-dilates, slows RHR, lowers BP, and improves heartrate variability (18,19). Notably, the circadian peak ofSNS activity usually occurs in the hours just beforeand after awakening in the morning, which correlates
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closely with the riskiest period during the 24-hourdaily cycle for myocardial infarction (MI), suddencardiac death (SCD), and stroke (18,20).
Because the patients treated with ADHD medi-cations are usually young with resilient CV healthat baseline and because most of the publishedstudies were of short duration and showed fewadverse events, medical professionals and thegeneral public typically consider sympathomimeticamines to be exempt from CV effects. However,other sympathomimetic drugs used for asthma,heart failure, and hypotension have been associatedwith increased risk of CV events, particularlyamong patients with existing CV disease (CVD) (18).Furthermore, ADHD medications have been shownto adversely affect the autonomic nervous systemby decreasing heart rate variability and increasingarterial stiffness (21).
ADHD DRUGS RAISE BP AND RHR
Generally, studies have found that amphetaminesand methylphenidate increase RHR and systolic BP. A Q
meta-analysis of 10 clinical trials reported that ADHDmedications significantly increased RHR by þ5.7beats/min, and systolic BP by 2.0 mm Hg (22). In-crements in RHR are directly correlated with higherrates of CVD and mortality during follow-up exami-nations in epidemiological studies (23), althoughspecific data regarding the risks of pharmacologicallyinduced rises in RHR are lacking (24–26).
Use of methylphenidate in a randomized placebo-controlled trial (RCT) has been associated with 4-fold increased odds of developing prehypertensionin previously normotensive adults (27). The mostrecent American College of Cardiology guidelinesrecommend that, for patients with hypertension whoare taking ADHD drugs, physicians should eitherdecrease the dose of these sympathomimetic amines
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Q3FIGURE 1 Comparative Prevalence of ADHD Medication Use Internationally
Prev
alen
ce (P
er 10
0)
8
6
4
2
02001 2003 20072005 2009 2011 2013 2015
Canada
USU.S. Medicaid
UK DenmarkSwedenFinland
FranceAustralia
JapanIceland
SpainHong Kong
TaiwanNorway
Overall annual prevalence of attention-deficit/hyperactivity disorder (ADHD) medication use in children 3 to 18 years of age (16). UK ¼ United
Kingdom.
J A C C V O L . - , N O . - , 2 0 2 0 Torres-Acosta et al.- , 2 0 2 0 :- –- Cardiovascular Effects of ADHD Therapies
or discontinue the medications altogether becausethey may cause elevated BP (28).
RISK OF ADVERSE CV EVENT STUDIES OF CV
SAFETY IN CHILDREN AND YOUNG ADULTS. Thesafety data considered by the FDA in 2011 for ADHDtreatment in children was based on a retrospectivecohort from insurance data, including 1,200,438subjects 2 to 24 years of age and a mean follow-up of2.1 years. That study found no increased risk ofadverse CV events (MI, SCD, or stroke) with use ofstimulants (29).
A longitudinal, prospective, nationwide cohortstudy focused on all children born in Denmark be-tween 1990 and 1999 with a mean follow-up of 9.5years. Among all the children with ADHD (n ¼ 8,300),there was an increased risk of adverse CVD eventsincluding arrhythmia (23%), cerebrovascular disease(9%), hypertension (8%), ischemic heart disease (2%),heart failure (2%), and pulmonary hypertension(<1%) in a comparison of ADHD prescription medi-cation users versus nonusers (adjusted hazard ratio:2.3; 95% confidence interval [CI]: 1.2 to 4.8) (30).
A case series using the South Korean nationalhealth insurance claims database included 1,224 pa-tients 17 years of age or younger who had been
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treated with methylphenidate for a mean of 6 months(31). That study found increased risk of arrhythmia inall exposure periods (adjusted incidence ratio: 1.6;95% CI: 1.4 to 1.7), although the highest risk wasobserved during the first week after initiation ofmethylphenidate therapy. Also, in the subgroupanalysis, the risk for arrhythmia was higher for pa-tients with congenital heart disease (31).
In a retrospective cohort study of 55,383 subjects 3to 20 years of age with a mean follow-up of31 months, use of ADHD medication was associatedwith a 20% increased risk for emergency departmentvisits due to cardiac causes (syncope 34%, arrhythmia33%, tachycardia and palpitation 16%, and hyperten-sive disease 15%). However, the number of eventswas too small for meaningful statistical analysis forrisk of CV death (32).
Olfson et al. (6) conducted a retrospective cohortincluding 171,000 subjects 6 to 21 years of age andfound no increased of risk cardiac events (includingangina pectoris, cardiac dysrhythmias, transientischemic attack) or cardiac symptoms (includingtachycardia, palpitations, and syncope) (6).
Over the past 3 decades, sporadic cases of SCD havebeen reported among children using methylpheni-date or amphetamines for ADHD (33,34). A matched
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CENTRAL ILLUSTRATION Q4Cardiovascular Effects of Attention-Deficit/Hyperactivity Disorder Therapies
Omega-3Psychostimulants
Physical activity
Improve autonomictone
Amphetamineassociated
cardiomyopathy
Suddencardiacdeath
TakotsuboCM ArrhythmiasMIHypertension
CV events
ArrhythmogenicpotentialVasoconstriction
SNSoverstimulation
Attention-Deficit/Hyperactivity Disorder
Torres-Acosta, N. et al. J Am Coll Cardiol. 2020;-(-):-–-.
Psychostimulant Q11activation of the sympathetic nervous system (SNS) leads to increments in resting heart rate and blood pressure as well as vasoconstriction and
arrhythmogenic potential. The outcome of SNS stimulation could potentially result in hypertension, increment in cardiovascular mortality, myocardial infarction (MI),
arrythmia episodes, sudden cardiac, Takotsubo and amphetamine-associated cardiomyopathy. The effects of nonpharmacological strategies such as physical activity
and omega-3 are cardioprotective by improvements in autonomic tone. Cardiovascular (CV) risk, SNS, Takotsubo cardiomyopathy (TCM), and MI. [ ¼ increases;
Y ¼ decreases; BP ¼ blood pressure; CM ¼ cardiomyopathy. Q12
Torres-Acosta et al. J A C C V O L . - , N O . - , 2 0 2 0
case-control study of individuals 7 to 19 years of agefound an increased risk of SCD in the group takingsympathomimetic stimulants (35). To eliminate theuncertainty related to recall bias, a subgroup analysisof this study was performed based solely on caseswith autopsy, toxicology, and medical examiner re-ports; analysis still showed a positive associationbetween ADHD medications and SCD (35).
STUDIES OF CV SAFETY IN ADULTS. One study usedby the FDA for safety, conducted by Habel et al. (36),is the largest and most comprehensive study per-formed in adults. That study used a design similar tothe study by Habel et al. (36) including 443,198 adults25 to 64 years of age with a median use of 4 monthsand follow-up of 1.3 years. They reported that,
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although the overall CV risk was not increased inpeople with a history of ADHD medication use,adverse CVD events (MI, SCD, or stroke) trendedinsignificantly higher in patients who had recentlystarted ADHD medications (36). Unexpectedly, thecurrent use of ADHD medications was protectiveagainst a composite of CV events (MI, SCD, or stroke)compared to nonuse (36).
A cohort study consisting of 43,999 individualswho were at least 18 years of age compared methyl-phenidate users to matched nonusers with a medianfollow-up of only 60 days (14). Among methylpheni-date users, there was a significantly higher risk forSCD or ventricular arrhythmia (14). Moreover, a sig-nificant association was found for all-cause mortality,although similar trends were not found for stroke or
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FIGURE 2 Omega-3 Effects on ADHD Symptoms Versus Placebo
−0.5 0.1
Inattention
Hyperactivity
Omega-3Better
PlaceboBetter
Total ADHD Symptoms
0.42 (0.23-0.62)
ES (95% CI)
0.48 (0.01-0.95)
0.38 (0.20-0.56)
0.3−0.3 −0.1 0.5 0.7 0.9 1.1
Forest plots showing total effect sizes from pooled results comparing attention-deficit/hyperactivity disorder (ADHD) clinical symptoms in the
omega-3 group and the and placebo group (53). CI ¼ confidence interval; ES Q9¼ ---
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FIGURE 3 EPA Dose and Treatment Efficacy for Attention-Deficit/Hyperactivity
Disorder
Effec
t Siz
e
0.75
0.5
0.25
0
0 300 450150EPA Dose (in mg)
600 750
Scatterplot displays the measured efficacy of omega-3 fatty acid supplementation in
trials as a function of eicosapentaenoic acid (EPA) dose used. The size of the circle in-
dicates trial weight obtained through generic inverse variance method (54).
J A C C V O L . - , N O . - , 2 0 2 0 Torres-Acosta et al.- , 2 0 2 0 :- –- Cardiovascular Effects of ADHD Therapies
MI. A year later, the same group of investigators,Schelleman et al. (37) found no increased risk of SCD/ventricular arrhythmia, stroke, MI, or all-cause deathassociated with the use of amphetamines or atom-oxetine in adults with short median follow-up periodsof 88 and 60 days, respectively.
A study of patients 65 years of age and older whowere taking ADHD medications showed increased riskof 1 case of new heart failure per 10.5 person-years ofstimulant use, with the symptoms usually appearingwithin the first 90 days of initiation of the ADHDmedication (13). Not surprisingly, older patients werefar more likely to present with new heart failure orcardiomyopathy than younger patients, and the olderpatients tended to present earlier after ADHD druginitiation (13). ADHD medications have been associ-ated with acute coronary syndrome in the setting ofnormal coronary arteries on angiography (38,39).Stress-induced cardiomyopathy, also referred to asTakotsubo cardiomyopathy, has also been reported inpatients taking ADHD medications (40,41).
As presented above, the current evidence is mixedregarding associations with CV events. All thesestudies have different age groups, outcomes, and useof medications. Three of the 6 studies were per-formed in children and adolescents, whereas 2 of the4 studies performed in adults were negative. Futureresearch needs to be done on very large cohorts as theincidence of these events is low and would be veryhard to demonstrate on RCTs. Also, study samples
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should be enhanced with older adults as well as thoseat a high risk for CV disease. A longer follow-up maybe required to assess chronic risks as the majority ofthe studies had follow-up times ongoing for1 to 2years in comparison.
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FIGURE 4 Exercise and Attention-Deficit/Hyperactivity Disorder Symptoms
−1 0 1−2Favors Control Favors Exercise
2
Subtotal (95% CI)
Kang et al. (2011)Chang et al. (2012)Verret et al. (2012)Mackune et al. (2013)Choi et al. (2015)
Exercise is another natural and benign nondrugtreatment for ADHD. Exercise has immediate andlong-term positive effects on behavioral and cogni-tive measurements in patients with ADHD (42). Thepotential benefits of exercise for ADHD are likely dueto the increase of norepinephrine, dopamine, andserotonin levels in the prefrontal cortex during and
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after physical activity (43). Also, brain-derived neu-rotrophic factors, synaptic proteins, glutamate re-ceptors, and insulin-like growth factor all rise duringand after strenuous physical activity, which improvescognitive function by contributing to cell prolifera-tion and neural plasticity (42).
Ahmed and Mohamed (44) conducted an RCTinvolving 84 students in a 10-week aerobic exerciseprogram for students with ADHD. After 10 weeks, the
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J A C C V O L . - , N O . - , 2 0 2 0 Torres-Acosta et al.- , 2 0 2 0 :- –- Cardiovascular Effects of ADHD Therapies
intervention group had significant improvements inattention, motor skills, and academic/classroombehavior with no improvements on task orientationor emotional and oppositional behavior. Acomprehensive meta-analysis of 8 RCTs (n ¼ 249)reported that aerobic exercise significantlyimproved attention, hyperactivity, impulsivity,anxiety, executive function, and social disorders(see Figure 3) (45). Estimates from RCT data indi-cate that the dose of physical activity for treatingADHD should entail bouts of high-intensity aerobicexercise lasting at least 30 minutes, at least 3 to 5times per week (42,43,46). However, this is stillsomewhat speculative, and the dose of exerciserequired to achieve a significant therapeutic effecton ADHD appears to vary by sex. Males appear torequire high-intensity exercise to achieve signifi-cant changes in brain dopaminergic activity,whereas females perform better after submaximalexercise (46). Even with the current uncertainties, aregular exercise program has been proposed as analternative to ADHD medications or as an adjuvantto pharmacotherapy that may help to lower thedoses and frequency of use for ADHD medications(Central Illustration) (43).
OMEGA-3 USED TO MODIFY ADHD
Omega-3 polyunsaturated fatty acids are found inhigh concentrations in the phospholipids of theneuronal and myocardial cell membranes, givingfluidity to the membranes and altering the function ofmembrane-bound proteins (47). Tellingly, omega-3deficiency in animal studies is associated withreduced levels of dopamine and serotonin in thefrontal cortex (47). Also, children with ADHD havebeen found to have significantly lower levels ofomega-3 than controls (48). There have been severalsmall RCTs of omega-3 for treating ADHD symptoms,with mixed results regarding its effectiveness; someof the trials were encouraging, while others werenegative (49–52).
A meta-analysis of 7 RCTs including 534 youngpatients found that omega-3 supplementationsignificantly improved parental reports of inatten-tion, hyperactivity, and total symptom scores(Figure 2) (53). Also, omega-3 improved total ADHDsymptoms with a modest effect size (ES) and reducedomission/commission errors with a large ES (53). Onlystudies with eicosapentaenoic acid (EPA) doses>500 mg/day consistently showed improvements in
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hyperactivity symptoms (53). Another meta-analysisof omega-3 for ADHD, which included 10 RCTs of699 children, found a modest but statistically signif-icant ES of 0.31 for improving ADHD symptoms (54).An even larger meta-analysis of 16 studies of 1,408children also found modest ES (0.26; 95% CI: 0.15 to0.37) of omega-3 on the pooled composite of ADHDsymptoms. Although omega-3 consistently reducedhyperactivity-impulsivity, it did not improve inat-tention behavior (55).
In most ADHD studies to date, the total dailyomega-3 dose was approximately 500 mg, whichproduced an ES of approximately 0.36 (54). Forreference, methylphenidate (ES ¼ 0.78; 95% CI: 0.64to 0.91) and atomoxetine (ES ¼ 0.64; 95% CI: 0.51 to0.76) show larger improvements in ADHD symptoms(54). However, a large body of RCT data indicate thatthe benefits of omega-3 for reducing CV risk weredose-dependent and linear, whereby every 1 gram/day docosahexaenoic acid (DHA) plus 4 grams/dayEPA showed the best results, reducing risk of majorCVD events by 8% (56). Similarly, higher doses of EPAappear to be associated with increasing efficacy intreating ADHD symptoms (Figure 3), suggesting thatlarger doses of omega-3 may be needed for optimalADHD treatment as well. The current data suggestthat the use of omega-3 may be reasonable toaugment the efficacy of conventional therapies or asan option for families who decline stimulants, butmore research with higher doses of omega-3 areneeded to clarify these issues.
CONCLUSIONS
Although the prevalence of ADHD has been stable forthe past 3 decades, the use of sympathomimetic drugsin the United States has been on the rise. ADHDmedications increase RHR and BP and are associatedwith increased risks of CVD. Promising alternativetreatments for ADHD include omega-3 and exercise.More high-quality prospective research is needed toexplore the potential dangers of ADHD medications inboth the children and adult populations and to eval-uate nonpharmacological treatments for ADHD thathave less potential for cardiac toxicity.
ADDRESS FOR CORRESPONDENCE: Dr. James H.O’Keefe, Mid America Heart Institute, 4321 Washing-ton Street, Suite 2400, Kansas City, Missouri 64111.E-mail: [email protected]. Twitter:@MidAmericaHeart.
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KEY WORDS ADHD, amphetamine salts,amphetamines, arrhythmia, atomoxetine,attention-deficit/hyperactivity disorder,cardiomyopathy, cardiotoxicity, exercise,lisdexamfetamine, methylphenidate, omega-3, sudden death
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