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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 ..."
The Background:
Meta-analyses have previously suggested a link between maternal thyroid dysfunction and neurodevelopmental disorders (NDDs) in children, though some studies report no significant difference. Overweight and obesity are more common in children and adolescents with NDDs. Hypothyroidism is often associated with obesity, which may result from reduced energy expenditure or disrupted hormone signaling affecting growth and appetite. These hormone-related parameters could potentially serve as biomarkers for NDDs; however, research findings on these indicators vary.
The Study:
A Chinese research group recently released a meta-analysis examining the relationship between neurodevelopmental disorders (NDDs) and hormone levels – including thyroid, growth, and appetite hormones – in children and adolescents.
The analysis included peer-reviewed studies that compared hormone levels – such as thyroid hormones (FT3, FT4, TT3, TT4, TSH, TPO-Ab, or TG-Ab), growth hormones (IGF-1 or IGFBP-3), and appetite-related hormones (leptin, ghrelin, or adiponectin) – in children and adolescents with NDDs like ADHD, against matched healthy controls. To be included, NDD cases had to be first-diagnosis and medication-free, or have stopped medication before testing. Hormone measurements needed to come from blood, urine, or cerebrospinal fluid samples, and all studies were required to provide both means and standard deviations for these measurements.
Meta-analysis of nine studies encompassing over 5,700 participants reported a medium effect size increase in free triiodothyronine (FT3) in children and adolescents with ADHD relative to healthy controls. There was no indication of publication bias, but variation between individual study outcomes (heterogeneity) was very high. Further analysis showed FT3 was only significantly elevated in the predominantly inattentive form of ADHD (three studies), again with medium effect size, but not in the hyperactive/impulsive and combined forms.
Meta-analysis of two studies combining more than 4,800 participants found a small effect size increase in thyroid peroxidase antibody (TPO-Ab) in children and adolescents with ADHD relative to healthy controls. In this case, the two studies had consistent results. Because only two studies were involved, there was no way to evaluate publication bias.
The remaining thyroid hormone meta-analyses, involving 6 to 18 studies and over 5,000 participants in each instance, found no significant differences in levels between children and adolescents with ADHD and healthy controls.
Meta-analyses of six studies with 317 participants and two studies with 192 participants found no significant differences in growth hormone levels between children and adolescents with ADHD and healthy controls.
Finally, meta-analyses of nine studies with 333 participants, five studies with 311 participants, and three studies with 143 participants found no significant differences in appetite-related hormone levels between children and adolescents with ADHD and healthy controls.
The Conclusion:
The team concluded that FT3 and TPO-Ab might be useful biomarkers for predicting ADHD in youth. However, since FT3 was only linked to inattentive ADHD, and TPO-Ab’s evidence came from just two studies with small effects, this conclusion may overstate the meta-analysis results.
Our Take-Away:
Overall, this meta-analysis found only limited evidence that hormone differences are linked to ADHD. One thyroid hormone (FT3) was higher in children with ADHD—mainly in the inattentive presentation—but the findings varied widely across studies. Another marker, TPO-Ab, showed a small increase, but this came from only two studies, making the result less certain. For all other thyroid, growth, and appetite-related hormones, the researchers found no meaningful differences between children with ADHD and those without. While FT3 and TPO-Ab may be worth exploring in future research, the current evidence is not strong enough to consider them reliable biomarkers.
Background:
Recent progress in reproductive medicine has increased the number of children conceived via assisted reproductive techniques (ART). These include:
Although ART helps with infertility, there are concerns about its long-term effects on offspring, especially regarding neurodevelopment. Factors such as hormonal treatments, gamete manipulation, altered embryonic environments, as well as parental age and infertility, may influence brain development and raise the risk of neurodevelopmental and mental health disorders.
With previous studies finding conflicting results on a possible association between ART and increased risk of mental health disorders, an Indian research team has just published a new meta-analysis exploring this topic.
The Study:
Studies were eligible if they were observational (cohort, case-control, or cross-sectional), reported confounder-adjusted effect sizes for ADHD, and were published in English in peer-reviewed journals.
A meta-analysis of eight studies encompassing nearly twelve million individuals indicated a 7% higher prevalence of ADHD in offspring conceived via IVF/ICSI compared to those conceived naturally. The heterogeneity among studies was minimal, and no evidence of publication bias was observed.
The study’s 95% confidence interval ranged from 4% to 10%. Further analysis of five studies comprising almost nine million participants that distinguished outcomes by sex revealed that the increase in ADHD risk among female offspring was not statistically significant. In contrast, the elevated risk in male offspring persisted, though it was marginally significant, with the lower bound of the confidence limit at only 1%.
Results:
A meta-analysis of three studies (1.4 million participants) found a 13% higher rate of ADHD in children conceived via ovulation induction/intrauterine insemination (OI/IUI) compared to natural conception. The effect size, though doubled, remains small. Minimal heterogeneity and no publication bias were observed.
The team concluded, “The review found a small but statistically significant moderate certainty evidence of an increased risk of ADHD in those conceived through ART, compared to spontaneous conception. The magnitude of observed risk is small and is reassuring for parents and clinicians.”
Our Take-Away:
Overall, the meta-analysis points to a small, but measurable increase in ADHD diagnoses among children conceived through ART, but the effect sizes are modest and supported by moderate-certainty evidence. And we must always keep in mind that the researchers who wrote the original articles could not correct for all possible confounds. These findings suggest that while reproductive technologies may introduce slight variation in neurodevelopmental outcomes, the effects are small and uncertain. For families and clinicians, the results are generally reassuring: ART remains a safe and effective avenue to parenthood, and the results of this study should not be viewed as a prohibitive concern. Thoughtful developmental monitoring and open, evidence-based counseling can help ensure that ART-conceived children receive support that caters to their individual needs.
The Background:
Myopia is a growing global health concern linked to conditions like macular degeneration, glaucoma, and retinal detachment. Its prevalence has surged in recent decades; by 2050, an estimated 5 billion people will have myopia. The increase is especially marked in Asia – a survey in Taiwan reports that 84% of students aged 15 to 18 are myopic, with 24% severely affected.
Dopamine is an important neurotransmitter in the retina, involved in eye development, visual signaling, and refractive changes. The dopamine hypothesis, suggesting that retinal dopamine release helps prevent myopia, has emerged as a leading theory of myopia control.
Most studies show ADHD is highly heritable, often involving dopamine system genes. ADHD is strongly associated with dopaminergic abnormalities, especially in dopamine transporter function and release dynamics.
Medications for ADHD, like methylphenidate, atomoxetine, and clonidine, help regulate dopamine to reduce symptoms.
The Study:
Given dopamine’s critical involvement in both ADHD and myopia, a Taiwanese research team hypothesized that medications for ADHD that influence dopaminergic pathways may have a significant effect on myopia risk.
To evaluate this hypothesis, the team conducted a nationwide cohort study using data from Taiwan’s National Health Insurance (NHI) program, which covers 99% of the nation’s 23 million residents and provides access to comprehensive eye care and screenings. Taiwan requires visual acuity screenings beginning at age four, with annual examinations for school-aged children to promote the early detection of visual anomalies such as myopia.
Furthermore, ADHD medication and diagnosis are tracked through compulsory diagnostic codes. This permits an accurate assessment of the effects of dopaminergic medications on myopia risk.
Propensity score allocation using a multivariable logistic regression model was applied to reduce bias from confounding influences, pairing cohorts based on similar scores.
The Results:
Comparing 133,945 individuals with ADHD with an equal number without ADHD, untreated ADHD was associated with a 22% greater risk of myopia.
However, after adjusting for covariates (gender, age, insured premium, comorbidities, location, and urbanization level), the ADHD cohort receiving medication treatment showed a 39% decreased risk of myopia relative to the untreated ADHD cohort.
Narrowing this further to the ADHD cohort receiving dopaminergic medications reduced the risk of myopia by more than half (52%) relative to the untreated ADHD cohort.
Treatment with two dopaminergic medications reduced the risk by well over two-thirds (72%) relative to the untreated ADHD cohort.
There were no significant differences between methylphenidate, atomoxetine, and clonidine. Each reduced risk by about 50%.
The team did not directly compare the ADHD cohort receiving dopaminergic medications with the non-ADHD cohort. But if there were 122 cases of myopia in the ADHD cohort for every 100 cases in the non-ADHD cohort, and dopaminergic medications halved the cases in the ADHD cohort to about 60, that would represent a roughly 40% reduction in myopia risk relative to the non-ADHD cohort.
The team concluded, “our research indicates that pharmacologically treated ADHD children have a reduced risk of myopia. Conversely, untreated ADHD children are at a heightened risk relative to those without ADHD. Moreover, the cumulative effects of ADHD medications were found to notably decrease myopia incidence, emphasizing the protective influence of dopaminergic modulation in these interventions.”
The Take-Away:
Children with untreated ADHD are more likely to develop myopia, but those receiving dopaminergic medications had a substantially lower risk. The findings suggest that ADHD medications may help protect against myopia by boosting dopamine signaling. More research is needed before firmly drawing this conclusion, but this research could open the door to new approaches for preventing myopia in at-risk children.
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