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November 16, 2023
The US Center for Disease Control's (CDC)review of ADHD starts with the statement: "Attention-deficit/hyperactivity disorder (ADHD) is a serious public health problem affecting many children and adults" (http://www.cdc.gov/ncbddd/adhd/research.html). My colleagues and I recently reviewed the ADHD literature. That let us describe ADHD as "... a seriously impairing, often persistent neurobiological disorder of high prevalence..." (Faraone et al., 2015). The figure 1, which comes from that paper, provides an overview of the lifetime trajectory of ADHD-associated morbidity.
Especially compelling data about ADHD and injuries comes from a recent paper, in Lancet Psychiatry, which used the Danish national registers to follow a cohort of 710,120 children (Dalsgaard et al., 2015a). Compared with children not having ADHD, those with ADHD were 30% more likely to sustain injuries than other children. Pharmacotherapy for ADHD reduced the risk for injuries by 32% from 5 to 10 years of age. Pharmacotherapy for ADHD reduced emergency room visits by 28.2% at age 10and 45.7% at age 12.
These results are shown in Figure 2, taken from the publication.
Especially compelling data about ADHD and injuries comes from a recent paper, in Lancet Psychiatry, which used the Danish national registers to follow a cohort of 710,120 children (Dalsgaard et al., 2015a). Compared with children not having ADHD, those with ADHD were 30% more likely to sustain injuries than other children. Pharmacotherapy for ADHD reduced the risk for injuries by 32% from 5 to 10 years of age. Pharmacotherapy for ADHD reduced emergency room visits by 28.2%at age 10and 45.7% at age 12.
These results are shown in Figure2, taken from the publication. The Figure compares the prevalence of injuries among three groups. ADHD children treated with medication, ADHD children not treated with medication, and children without ADHD. The Figure shows how ADHD risk for injuries occurs for all age groups. It also shows how the risk for injuries drops with treatment so that by age 12, the prevalence of injuries among treated ADHD children is the same as the prevalence of injuries for children without ADHD.
Documented examples of ADHD-associated injuries which impact day-to-day functioning include severe burns (Fritz and Butz, 2007), dental injuries (Sabuncuoglu, 2007), penetrating eye injuries (Bayar et al., 2015), the hospital treated injuries (Hurtig et al., 2013), and head injuries (DiScala et al., 1998). In one study (DiScala et al., 1998), when compared to other children admitted to the hospital for injuries, ADHD children were more likely to sustain injuries in multiple body regions (57.1% vs 43%), sustain head injuries (53% vs 41%), and to be severely injured as measured by the Injury Severity Score (12.5% vs5.4%) and the Glasgow Coma Scale (7.5% vs 3.4%).
Injuries are a substantial cause of ADHD-associated premature death. This assertion comes from the work of Dalsgaard et al. (2015b)based on the same Danish registry discussed above. In this second study, ADHD was associated with an increased risk for premature death and 53% of those deaths were due to injuries. They reported the risk for premature death in three age groups: 1-5, 6-17, and >17. For all three age groups, they found a greater risk for death in the ADHD group. For ages 6 to 17 and greater than 17. The ADHD-associated risk for mortality remained significant after excluding individuals with antisocial or substance use disorders.
There are currently no data about the effect of ADHD treatment on ADHD-associated premature death. We do, however, know from the data reviewed above that ADHD treatment reduces injuries and that half the deaths in the ADHD group were due to injuries. From this, we infer that ADHD treatments could reduce the risk of ADHD-associated premature death.
Two other ADHD-associated mobilities, obesity and cigarette smoking, have clear medical consequences. In a meta-analysis of 42 cross-sectional studies comprising 48,161 people with ADHD and 679,975 controls, my colleagues and I reported that the pooled prevalence of obesity was increased by about 40% in ADHD children compared with non-ADHD children and by about 70% in ADHD adults compared with non-ADHD adults(Cortese et al.,2015). The association between ADHD and obesity was significant for ADHD medication-naïve subjects but not for those medicated for ADHD, which suggests that medication reduces the risk for obesity.
Likewise, a meta-analysis of 27 longitudinal studies assessed the risk for several addictive disorders with sample sizes ranging from 4142 to 4175 for ADHD and 6835 to 6880 for non-ADHD controls (Lee et al., 2011). Children with ADHD were at higher risk for disorders of abuse or dependence on nicotine, alcohol, marijuana, cocaine, and other unspecified substances. Another meta-analysis (42 studies totaling, 2360 participants) showed that medications for ADHD reduced the ADHD-associated risk for smoking (Schoenfelder et al., 2014). The authors concluded that, for ADHD patients, "Consistent stimulant treatment for ADHD may reduce the risk of smoking". This finding is especially notable given that, for ADHD youth, cigarette smoking is a gateway drug to more serious addictions (Biederman et al., 2006).
Yes, ADHD is a serious disorder. Although most ADHD people will be spared the worst of these outcomes, they must be considered by parents and patients when weighing the pros and cons of treatment options.
Bayar, H., Coskun, E., Oner, V., Gokcen,C., Aksoy, U., Okumus, S. & Erbagci, I. (2015). Association between penetrating eye injuries and attention deficit hyperactivity disorder in children.Br J Ophthalmol99, 1109-11.
Biederman, J., Monuteaux, M., Mick, E., Wilens, T., Fontanella, J.,Poetzl, K. M., Kirk, T., Masse, J. & Faraone, S. V. (2006). Is cigarette smoking a gateway drug to subsequent alcohol and illicit drug use disorders? A controlled study of youths with and without ADHD. Biol Psychiatry59, 258-64.
Cortese, S., Moreira-Maia, C. R., St Fleur, D., Morcillo-Penalver, C.,Rohde, L. A. & Faraone, S. V. (2015). Association Between ADHD and Obesity: A Systematic Review and Meta-Analysis. Am J Psychiatry, appiajp201515020266.
Dalsgaard, S., Leckman, J. F., Mortensen, P. B., Nielsen, H. S. &Simonsen, M. (2015a). Effect of drugs on the risk of injuries in children with attention deficit hyperactivity disorder: a prospective cohort study. Lancet Psychiatry2, 702-9.
Dalsgaard, S., Ostergaard, S. D., Leckman, J. F., Mortensen, P. B.& Pedersen, M. G. (2015b). Mortality in children, adolescents, and adults with attention deficit hyperactivity disorder: a nationwide cohortstudy. Lancet385, 2190-6.
DiScala, C., Lescohier, I., Barthel, M. & Li, G. (1998).Injuries to children with attention deficit hyperactivity disorder. Pediatrics102, 1415-21.
Faraone, S. V., Asherson, P., Banaschewski, T., Biederman, J.,Buitelaar, J. K., Ramos-Quiroga, J. A., Rohde, L. A., Sonuga-Barke, E. J. S.,Tannock, R. & Franke, B. (2015). Attention deficit hyperactivitydisorder. In Nature Reviews: DiseasePrimers.
Fritz, K. M. & Butz, C. (2007). Attention Deficit/Hyperactivity Disorder and pediatric burn injury: important considerations regarding premorbid risk. Curr Opin Pediatr19, 565-9.
Hurtig, T., Ebeling, H., Jokelainen, J., Koivumaa-Honkanen, H. &Taanila, A. (2013). The Association Between Hospital-Treated Injuries and ADHD Symptoms in Childhood and Adolescence: A Follow-Up Study in the Northern Finland Birth Cohort 1986. J Atten Disord.
Lee, S. S., Humphreys, K. L., Flory, K., Liu, R. & Glass, K. (2011).Prospective association of childhood attention-deficit/hyperactivity disorder(ADHD) and substance use and abuse/dependence: a meta-analytic review. Clin Psychol Rev31, 328-41.
Sabuncuoglu, O. (2007). Traumatic dental injuries and attention-deficit/hyperactivity disorder: is there a link? Dent Traumatol23,137-42.
Schoenfelder, E. N., Faraone, S. V. & Kollins, S. H. (2014).Stimulant treatment of ADHD and cigarette smoking: a meta-analysis. Pediatrics133, 1070-1080.
Methylphenidate is an effective treatment for ADHD in adults who also have bipolar disorder (BD), but it carries a potential risk of triggering manic episodes. Current guidelines therefore recommend using it only alongside mood-stabilizing medication. A new study using French nationwide claims data sought to test and extend those recommendations with greater statistical power than previous research.
The study built on findings by Viktorin et al. (2017), who observed that adults with BD not taking mood stabilizers had more than a sixfold higher risk of manic events (defined as hospitalization for mania or a new antimanic prescription) within six months of starting methylphenidate. Patients on mood-stabilizing treatment, by contrast, showed nearly half the baseline risk in the first three months. Those findings were limited, however, by small event counts (fewer than 61 manic episodes) and an effect that did not persist beyond the initial three-month window.
To build on this, researchers drew on the French National Health Data System (which is a claims database covering more than 60 million people) spanning 2008 to 2024. The final sample included 6,022 adults with BD (56% women) who had started methylphenidate. Using a self-controlled design, the study compared each patient's rate of manic events in the six months before their first methylphenidate prescription with the rate in the six months after, effectively eliminating stable individual differences as a confound.
Patients were classified as receiving continuous mood-stabilizing treatment if they had been dispensed at least two courses of specific antipsychotics (aripiprazole, olanzapine, or quetiapine) or mood stabilizers (lithium or valproate) in the nine months before starting methylphenidate, including at least one dispensation in the final six months of that window.
The results largely confirmed the earlier findings. Among the 2,745 patients not on mood stabilizers, the rate of inpatient mania diagnosis was 5.1 times higher in the first three months after starting methylphenidate, though this elevation fell to a non-significant level over the subsequent three months. Patients receiving continuous mood-stabilizing treatment showed no statistically significant change in mania risk across the full six-month post-initiation period. A formulation-specific pattern also emerged: patients without mood-stabilizing treatment had a 2.5-fold higher risk associated with extended-release methylphenidate, while no significant risk increase was seen with the immediate-release formulation or in treated patients regardless of formulation.
The authors conclude that methylphenidate at doses below 30 mg does not appear to elevate manic relapse risk when prescribed alongside mood stabilizers. The elevated risk seen in untreated patients, particularly with extended-release formulations, must be interpreted cautiously, given limited statistical power and the likelihood that it partly reflects the natural fluctuation of manic relapse over time. The authors flag this as an inherent limitation of self-controlled survival analyses when studying drug-induced mania, where temporal trends in the underlying condition can be difficult to disentangle from treatment effects.
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.
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