April 24, 2024
Are attention-deficit/hyperactivity disorder (ADHD) medications associated with risk of cardiovascular disease (CVD)?
An international study team has just explored this question with a meta-analysis of nineteen studies with a total of almost four million participants of all ages. It included 3,931,532 participants from six countries or regions: United States, South Korea, Canada, Denmark, Spain, and Hong Kong.
Overall, using the entire data set, it found no significant association between any ADHD medication use and any cardiovascular event.
The same held true when breaking this down by children and adolescents (twelve studies with over 1.7 million participants), young and middle-aged adults (seven studies with over 850,000 participants), and older adults (six studies with over a quarter million participants).
The team then compared the data for stimulant medications with data for non-stimulant medications. A meta-analysis of 17 studies with over 3.8 million participants found no significant association between stimulant medications and cardiovascular risk. Similarly, a meta-analysis of three studies with over 670,000 participants found no significant association between non-stimulant medications and cardiovascular risk.
Distinguishing between types of cardiovascular risk made no difference. For instance, a meta-analysis of nine studies with over 900,000 participants found no effect of stimulant medications on risk of myocardial infarction (heart attack), and a meta-analysis of six studies, also with over 900,000 participants, found no effect of stimulant medications on risk of cerebrovascular disease, including stroke, brain aneurysm, brain bleed, and carotid artery disease. A meta-analysis of eight studies with over 1.1 million participants did find an increase in the occurrence of cardiac arrest and tachyarrhythmias (racing heart rate accompanied by arrhythmias), but it was not statistically significant.
A meta-analysis of eleven studies with over 3.1 million persons with no prior history of cardiovascular disease found absolutely no effect of ADHD medications on subsequent risk for any cardiovascular event. Another meta-analysis, of eight studies encompassing over 1.8 million individuals with a prior history of cardiovascular disease, reported a higher rate of subsequent occurrence, but it was not considered statistically significant.
The team concluded, “Overall, our meta-analysis provides reassuring data on the putative cardiovascular risk with ADHD medications.” An international team of researchers recently investigated whether medications for attention-deficit/hyperactivity disorder (ADHD) are linked to an increased risk of cardiovascular disease (CVD). They conducted a comprehensive review, known as a meta-analysis, which included 19 studies with nearly four million participants from six countries or regions: the United States, South Korea, Canada, Denmark, Spain, and Hong Kong.
The findings from the entire data set showed no significant link between the use of any ADHD medications and the occurrence of cardiovascular events. This lack of association was consistent across all age groups: children and adolescents (12 studies with over 1.7 million participants), young and middle-aged adults (7 studies with over 850,000 participants), and older adults (6 studies with over 250,000 participants).
The researchers also compared the effects of stimulant medications against non-stimulant medications on cardiovascular risk. Both categories showed no significant risks in a meta-analysis of 17 studies with more than 3.8 million participants for stimulants, and three studies with over 670,000 participants for non-stimulants.
Further analysis differentiated between types of cardiovascular risks, such as myocardial infarction (heart attack) and cerebrovascular diseases (like stroke, brain aneurysm, and carotid artery disease). Again, stimulant medications showed no significant impact on these conditions in studies involving over 900,000 participants each. However, a review of eight studies with over 1.1 million participants suggested a slight increase in incidents of cardiac arrest and tachyarrhythmias (a racing heart rate with irregular rhythms), but these findings were not statistically significant.
Additionally, an analysis of 11 studies involving more than 3.1 million people without a prior history of cardiovascular disease found no effect of ADHD medications on the risk of developing cardiovascular events. Likewise, an analysis of eight studies with over 1.8 million individuals who had a history of cardiovascular disease showed a higher occurrence rate of events, but this increase was also not statistically significant.
The conclusion of the research team was clear: the data is reassuring and does not suggest a substantial cardiovascular risk associated with ADHD medications. Keep in mind that this reflects current standards of care. Most guidelines call for monitoring of pulse and blood pressure during treatment so that adverse cardiovascular outcomes can be avoided.
Le Zhang, Honghui Yao, Lin Li, Ebba Du Rietz, Pontus Andell, Miguel Garcia-Argibay, Brian M. D’Onofrio, Samuele Cortese, Henrik Larsson, Zheng Chang, “Risk of Cardiovascular Diseases Associated With Medications Used in Attention-Deficit/Hyperactivity Disorder: A Systematic Review and Meta-analysis,” JAMA Network Open (2022) 5(11), e2243597, https://doi.org/10.1001/jamanetworkopen.2022.43597.
Methylphenidate, a psychostimulant, is among the drugs most frequently prescribed to children with ADHD.
Using magnetic resonance imaging(MRI), studies have shown that as children mature, those with ADHD differ from controls in developing regionally thinner cortices (the folded outer layer of the cerebrum that is essential to rational thought) and smaller lower basal ganglia(structures linked to the thalamus in the base of the brain and involved in the coordination of movement). The cortical differences were found in the right medial frontal motor region, the left middle/inferior frontal gyrus, and the right posterior parieto-occipital region in children with ADHD who were not taking psychostimulants.
A Dutch/Norwegian team of researchers conducted a randomized, double-blind, placebo-controlled trial with 96 males recruited from Dutch clinical programs. 48 were boys aged 10-12 years, and 47 were men between the ages of 23 and 40. None had previously been on methylphenidate. There were no significant differences in baseline age, ADHD symptom severity, estimated intelligence quotient, the proportion of right-handedness, or region of interest brain characteristics between the placebo and medication groups.
The trial was carried out during the standard 17-week waiting list time for evaluation and treatment to begin so that those receiving a placebo during the trial would not ultimately be at a disadvantage. The same MRI scanner was used for all measurements, both before and after treatment.
Among the boys, the methylphenidate group showed increased thickness in the right medial cortex, while the placebo group showed cortical thinning. In adults, both groups showed cortical thinning. When converted into an estimated mean rate of change in cortical thickness for the right medial cortex, boys taking methylphenidate could expect to lose about 0.01 mm per year, versus about 0.14 mm for boys not on methylphenidate.
In the right posterior cortex, scans also showed reduced thinning in the methylphenidate treatment group, though to a lesser extent. But there was no reduced thinning in the left frontal cortex.
The authors noted several limitations. The sample size was small. Second, "because we did not detect significant relationships between changes in cortical [regions of interest] and changes in symptom severity, the functional significance remains uncertain." Third, the follow-up period was relatively short, not allowing any assessment of the longer-term effects of the medication. Fourth, the differences in effects on the three brain regions examined were uneven, contrary to what had been expected from previous studies. They recommended replication with larger groups and longer follow-ups.
A Chinese research team performed two types of meta-analyses to compare the risk of suicide for ADHD patients taking ADHD medication as opposed to those not taking medication.
The first type of meta-analysis combined six large population studies with a total of over 4.7 million participants. These were located on three continents - Europe, Asia, and North America - and more specifically Sweden, England, Taiwan, and the United States.
The risk of suicide among those taking medication was found to be about a quarter less than for unmediated individuals, though the results were barely significant at the 95 percent confidence level (p = 0.49, just a sliver below the p = 0.5 cutoff point). There were no significant differences between males and females, except that looking only at males or females reduced sample size and made results non-significant.
Differentiating between patients receiving stimulant and non-stimulant medications produced divergent outcomes. A meta-analysis of four population studies covering almost 900,000 individuals found stimulant medications to be associated with a 28 percent reduced risk of suicide. On the other hand, a meta-analysis of three studies with over 62,000 individuals found no significant difference in suicide risk for non-stimulant medications. The benefit, therefore, seems limited to stimulant medication.
The second type of meta-analysis combined three within-individual studies with over 3.9 million persons in the United States, China, and Sweden. The risk of suicide among those taking medication was found to be almost a third less than for unmediated individuals, though the results were again barely significant at the 95 percent confidence level (p =0.49, just a sliver below the p = 0.5 cutoff point). Once again, there were no significant differences between males and females, except that looking only at males or females reduced the sample size and made results non-significant.
Differentiating between patients receiving stimulant and non-stimulant medications once again produced divergent outcomes. Meta-analysis of the same three studies found a 25 percent reduced risk of suicide among those taking stimulant medications. But as in the population studies, a meta-analysis of two studies with over 3.9 million persons found no reduction in risk among those taking non-stimulant medications.
A further meta-analysis of two studies with 3.9 million persons found no reduction in suicide risk among persons taking ADHD medications for 90 days or less, "revealing the importance of duration and adherence to medication in all individuals prescribed stimulants for ADHD."
The authors concluded, "exposure to non-stimulants is not associated with a higher risk of suicide attempts. However, a lower risk of suicide attempts was observed for stimulant drugs. However, the results must be interpreted with caution due to the evidence of heterogeneity ..."
Maternal infections and inflammatory responses during pregnancy have been proposed as risk factors for neurodevelopmental disorders such as ADHD.
Taiwan has a single-payer health insurance system that covers virtually the entirety of its population. Its Ministry of Health and Welfare maintains the National Health Insurance Research Database (NHIRD), with detailed information on outpatient services, hospitalizations, and medical treatment for nearly 99% of all residents.
A Taiwanese study team used NHIRD to examine to examine the relationship between maternal hospitalization for infection, and early childhood infection, and subsequent ADHD in offspring. The study cohort originated with all 3,260,879 individuals born between 2001 and 2018.
The team excluded births from foreign mothers, still births, births with congenital defects, low birth weights, abnormally late births, twins, triplets, and other multiple births, culminating in a final population cohort of 2,885,662 live-born single infants across 1,893,171 families, and 1,864,660 individuals with full siblings from 872,169 families comprising the full sibling cohort.
Study participants were followed until diagnosis of a neurodevelopmental disorder, their death, or the end of 2021.
After adjusting for sex, birth year, paternal and maternal ages, birthweight, birth season, parity, delivery method, 1 minute APGAR score (evaluating baby’s appearance, pulse, grimace, activity and respiration at birth), gestational age, pregnancy and delivery complications, parental history of neurodevelopmental disorders, maternal asthma and diabetes, urbanization level of the residential area, and family’s insurance amount, offspring of mothers hospitalized for infections had 14% greater odds of being subsequently diagnosed with ADHD.
However, in the full sibling cohort of over 1.8 million, this association vanished. That held true for each of the three trimesters of pregnancy. It also held true for bacterial infections. Surprisingly, offspring of mothers hospitalized for viral infections were 24% less likely to be diagnosed with ADHD than their siblings not exposed to maternal viral infection. Because of that, they also had a 6% lower risk overall.
After the same adjustments, early childhood infection was associated with 16% greater odds of being diagnosed with ADHD.
Nevertheless, in the full sibling cohort of over 1.8 million, this association again vanished. That held true overall, as well as separately for childhood infections in months 1-6 and months 7-12. The association vanished altogether both for bacterial infections as well as for viral infections.
The authors concluded, “the results of this nationwide birth cohort study with population and sibling analyses suggest that the association between maternal infection during pregnancy and offspring neurodevelopmental risk is largely due to familial confounding factors.”
Most previous studies of suicide and self-harm risk among persons with ADHD have focused on adolescents and adults. They’ve also tended to be cross-sectional, analyzing data from a population at a specific point in time.
An Australian study team took a different approach, conducting a before-and-after study through the birth cohort of the Longitudinal Study of Australian Children (LSAC), comprising 5,107 children who have been followed up every two years since birth.
The diagnosis of ADHD was based on parents reporting that their child had received a diagnosis of ADHD at or before age ten.
Suicide and self-harm were defined as children’s self-report at age 14 of any thought or attempt of suicide and self-harm respectively over the past year.
The team adjusted for the following confounders: socioeconomic status, birth weight, ADHD medication history, maternal education level, maternal age at birth, experience in bullying victimization at age 12, and depression score based on Short Mood and Feelings Questionnaire (SMFQ).
Of the 5,107 participants, 3,696 had all the valid data required for analysis and were included in the final cohort. Of these, 3.6% were diagnosed with ADHD by age 10.
With diagnosis of ADHD at age 10 and all other factors held constant:
Both depression and exposure to bullying were statistically significant mediators for the relationship. Nevertheless, depression and exposure to bullying each accounted for well under 10% of the overall effect.
Neither socioeconomic status nor maternal factors had any significant mediating effect on outcomes.
Conclusion:
The authors concluded, “This study provides compelling evidence that children diagnosed with ADHD at the age of 10 years face significantly elevated risks of experiencing suicidal thoughts, planning, or attempts, as well as self-harm, by the age of 14 years, which underscores the critical importance of recognizing and addressing these heightened risks in children with ADHD.”
While factors like depression and bullying contribute, ADHD itself remains a key risk factor. Early intervention and strong mental health support are crucial to protecting these children’s well-being.
Noting that “Recent research has demonstrated that some gut bacteria can affect the nervous system,” and speculating that “dysregulation in the gut microbiota may increase the incidence of ADHD by overproducing reactive oxygen and nitrogen species, thereby causing neuroinflammation and oxidative stress”, a Taiwanese study team decided to explore whether early-life use of antibiotics – in the first two years – is associated with increased risk of subsequent diagnosis of ADHD.
Because Taiwan has a single-payer national health insurance system that covers 99.8% of the island’s population, they were able to use the system’s National Health Insurance Research Database (NHIRD) and Maternal and Child Health Database (TMCHD) to include all 1.6 million children born between 2004 and 2012.
Of these, a little over 1.1 million were given antibiotics before turning two years old, and just over 460,000 were not given antibiotics in the same time frame.
The mean follow-up period for records of subsequent ADHD diagnoses was seven years.
The team adjusted for confounding variables: sex, gestational age at birth (weeks), and birth weight (grams) of the children, and age at birth (years), insurance amount (New Taiwan Dollar (TWD)), insurance location, method of delivery, comorbidities, and medication used during pregnancy.
With these adjustments, early-life antibiotics use was associated with a 12% increase in likelihood of being subsequently diagnosed with ADHD.
However, looking at the effects of antibiotics as an undifferentiated grouping turned out to be misleading, because the association was limited to only some classes of antibiotics.
Penicillins were associated with a 22% increase in risk of subsequent ADHD diagnosis, cephalosporins with a 10% increase.
On the other hand, there was absolutely no such association for tetracyclines, macrolides, and quinolones.
The Take-Away:
This study found that children in Taiwan who took certain types of antibiotics before age 2 had a slightly higher risk of developing ADHD later in life. More work is needed to determine if this finding is due to unmeasured confounding before a causal link can be concluded.
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