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April 13, 2021
In the world of research, it is unusual for a single study to be definitive. A possible exception is a recent report in the highly esteemed Lancet, which concluded that people diagnosed with ADHD were about two times more likely to die early than people without ADHD. The data came from the medical registers of Denmark that include1.92 a million people, of which 32,061 have ADHD. The registers included the times and causes of deaths spanning 32 years.
It is a remarkable resource. We know that people with very severe ADHD are at high risk for substance use disorders and antisocial behaviors. In the Danish study, these disorders also increased the risk for premature death, but the risk was even higher if people with those disorders also had ADHD. ADHD also increased the risk for early death among people without these extra problems. This latter finding points to an ADHD-specific pathway to premature death. What is it? Well, we know that ADHD people are at risk for injuries, traffic accidents, and traumatic brain injury. We don't know for certain why, but two symptom clusters of ADHD, inattention, and impulsivity, would be expected to increase the risk for accidents and injuries. For example, adults who are distracted while driving are clearly at risk for accidents. Accidents accounted for most of the early deaths in the Danish study. But the study also found an increase in natural causes of death due to having ADHD. This may be due to the well-replicated association between ADHD and obesity, or the possibility that ADHD symptoms lead to poor health habits.
In the Danish study, the mean age at diagnosis was 12.3, which means that many of the ADHD people in the study were not treated for many years after the onset of symptoms. The risk for early death increased with the age at diagnosis. This suggests that failing to diagnose and treat ADHD early makes the disorder worse and increases the risk for the types of behaviors that lead to premature death. Will these data change public policy or clinician behavior? I hope so. Perhaps the media will stop trivializing ADHD and accept it as a bona fide disorder in need of early identification and treatment. Policymakers should allocate ADHD people their fair share of healthcare and research resources. For clinicians, early identification and treatment should become the rule rather than the exception.
Talk of premature death will worry parents and patients. That is understandable, but such worries can be alleviated by focusing on two facts: the absolute risk for premature death is low, and this risk can be greatly reduced by seeking and adhering to evidence-based treatments for the disorder.
Dalsgaard, S., Ostergaard, S. D., Leckman, J. F., Mortensen,P. B. & Pedersen, M. G. (2015). Mortality in children, adolescents, andadults with attention deficit hyperactivity disorder: a nationwide cohortstudy. Lancet.
Vaa T. ADHD and relative risk of accidents in road traffic:a meta-analysis. Accident; analysis and prevention.2014; 62: 415-25.
Adeyemo BO,Biederman J, Zafonte R, Kagan E, Spencer TJ, Uchida M, et al. MildTraumatic Brain Injury and ADHD: A Systematic Review of the Literature andMeta-Analysis. J AttenDisord. 2014; 18(7): 576-84.
Cortese S, Faraone SV, Bernardi S, Wang S, Blanco C. Adultattention-deficit hyperactivity disorder and obesity: epidemiological study. BrJ Psychiatry.2013; 203: 24-34.
Spencer TS, Faraone SV, Tarko L, McDermott K, Biederman J.ADHD and Adverse Health Outcomes in Adults: Results from a Large ControlledStudy. 2013.
Faraone SV. The scientific foundation for understandingattention-deficit/hyperactivity disorder as a valid psychiatric disorder.EurChild Adolesc Psychiatry.2005; 14: 1-10."
The FDA has approved a new once-daily pill called centanafadine (trade name SIMTRIYO®). Approved for adults and kids aged 6 and older (weighing at least 44 lbs / 20 kg), centanafadine is a new category of ADHD treatment that aims to give fast results with fewer of the downsides of traditional stimulants.
To understand why centanafadine is unique among medications for ADHD, it helps to look at how ADHD brain chemistry works:
Stimulants like Ritalin and Adderall work mainly in the dopamine system. Nonstimulants like atomoxetine, viloxazine, clonidine and guanfacine work mainly on the norepinephrine system. Centanafadine is the first drug in a new class called NDSRIs (Norepinephrine, Dopamine, and Serotonin Reuptake Inhibitors). We can describe its effects as follows:
What Did Clinical Trials Show?
The FDA approved centanafadine based on studies involving thousands of adults, teens, and children. Here are the key findings:
Centanafadine showed some improvement in ADHD symptoms within the very first week of taking it although a full effect takes about six weeks.
In adult trials, taking 200 mg or 400 mg daily led to significant improvements in real-world skills:
In trials with children (ages 6–12) and teens (ages 13–17), centanafadine significantly reduced core ADHD symptoms like hyperactivity, impulsivity, and lack of focus compared to a placebo.
About 30% to 40% of adults with ADHD also suffer from anxiety. Traditional stimulants can make anxiety worse. In a trial specifically designed for adults dealing with both ADHD and anxiety, centanafadine effectively treated ADHD symptoms without firing up their anxiety, which might be due to its serotonin boost.
Does Centanafadine have Side Effects?
While Centanafadine was well-tolerated by most people in studies, like any prescription medication, it comes with important safety guidelines.
Prescribing Warnings:
Common Side Effects:
Other Warnings:
The Bottom Line
Overall, centanafadine is a new step forward in how we treat ADHD. Because it acts differently in the brain than traditional treatments, patients who struggle with stimulant-related anxiety or side effects may find it useful to explore with their doctor.
A landmark nationwide study from South Korea has uncovered a significant link between prenatal exposure to air pollution — specifically nitrogen dioxide (NO2) — and an increased risk of ADHD in children.
While researchers have long suspected that air pollutants interfere with fetal brain development through inflammation and oxidative stress, this study is one of the largest and most comprehensive of its kind, following nearly 1.5 million births for up to 13 years.
Why South Korea?
South Korea provided a unique countrywide “laboratory” for this research due to two key infrastructure strengths:
Key Findings: The “Smoking Gun” of NO2
While the study looked at several pollutants, nitrogen dioxide — a byproduct of fossil fuel combustion in cars and power plants — emerged as the primary concern.
Pollutant
Association with ADHD Risk
Nitrogen Dioxide (NO2)
Strongest Link: Every 1-ppb (part-per-billion) increase in exposure linked to a 22% rise in risk.
Sulfur Dioxide (SO2)
Minimal Link: Only a slight 4% increase per ppb.
Ozone (O3) carbon monoxide (CO), & particulates
No significant association was found.
The scale of the NO2 risk is particularly striking. Over the typical range of exposure levels found in the study (an interquartile range of 13 ppb), the data suggest a threefold increase in ADHD risk for children in the highest-exposure groups compared to the lowest.
Accounting for Other Factors
To ensure the results weren’t skewed by other variables, the researchers controlled for a wide range of confounders including:
The authors emphasized the strong association between maternal nitrogen dioxide exposure and ADHD, while also noting the small but significant association with sulfur dioxide.
The Take-Away: A New Frontier for Public Health
Historically, air quality laws have been designed to protect our lungs and hearts. However, this study adds to a growing body of evidence suggesting that the brain is likewise vulnerable.
In a commentary on the findings, expert George Ayoub argued that “neurodevelopment should be explicitly considered” when governments perform cost-benefit analyses on air quality regulation. My view is a bit different. The association is intriguing but the study does not establish cause and effect. Many statistically significant environmental risk associations for neurodevelopmental disorders have disappeared after controlling for maternal risk for ADHD. I hope this research team will do those analyses if feasible.
Executive functions (EFs) are the cognitive control systems that allow people to pursue goals, make decisions, and adapt to changing circumstances. Researchers generally break them into three overlapping capacities: working memory (holding and manipulating information in mind), inhibitory control (suppressing impulses and filtering out distractions), and cognitive flexibility (switching between tasks or mental frameworks). Strong EFs in childhood predict academic achievement, social competence, and long-term mental health; weaknesses in these areas that go unaddressed can persist into adulthood, undermining school performance, career prospects, and well-being.
The Background:
Interest in training these skills has grown rapidly, but most research has been conducted in Western settings. China presents a distinctive context. Collectivist values make group-based programs culturally natural, and parental investment in academic outcomes is high. Both of these factors should, in theory, work in an intervention’s favor. At the same time, tightly scheduled school days (sessions typically capped at 30 minutes or less) constrain what is actually deliverable. A growing number of randomized controlled trials (RCTs) have tested EF interventions with Chinese children, but until now, no one has pulled that evidence together systematically.
The Study:
A new network meta-analysis did exactly that. The researchers screened RCTs involving Chinese children aged 3–12, including both typically developing children and those showing subclinical signs of ADHD or autism spectrum disorder (ASD), for instance, siblings of children with an ASD diagnosis. Children who already carried a formal neurodevelopmental diagnosis were excluded. Fifty-two trials covering nearly 3,000 children met the inclusion criteria. Interventions fell into four categories:
The headline finding is that three of the four intervention types produced statistically significant improvements across all three EF domains. The exception was the hybrid physical-cognitive program, which did not reach significance for inhibitory control. Positive results across the board might sound encouraging until you look at the actual effect sizes.
The Results:
The actual effects were negligible. Every significant result fell well below what methodologists define as a “small” effect (a standardized mean difference, or SMD, of 0.2). The largest effect size in the entire analysis was an SMD of 0.097 (less than half that threshold). The authors summarize the interventions’ effects as “modest,” but that is generous phrasing for numbers that, in practical terms, amount to very little. The analysis also showed signs of publication bias, meaning that studies with null or negative results may not have been published, potentially inflating even these modest figures.
The Take-Away:
It is important to note that these results don’t necessarily mean that this is the last word on EF training. The results apply specifically to Chinese children working within the time constraints of Chinese school schedules, and they exclude children with diagnosed ADHD, a population for whom cognitive interventions sometimes show larger effects. Generalizing beyond those boundaries is unwarranted.
What the findings do suggest is that structured EF programs, as currently implemented in Chinese educational settings, are not delivering meaningful real-world benefits. Statistical significance, it is worth remembering, is not the same as practical significance, and the gap between the two is sharp here.
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