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August 7, 2021
A team from Harvard Medical School and Massachusetts General Hospital conducted a six-week open-label trial of liquid-formulation extended-release methylphenidate (MPH-ER) to treat ADHD in adults with high-functioning autism spectrum disorder (HF-ASD). ASD is a lifelong disorder with deficits in social communication and interaction and restricted, repetitive behaviors. Roughly half of those diagnosed with ASD also are diagnosed with ADHD.
This was the first stimulant trial in adults with both ASD and ADHD. There were twelve males and three female participants, all with moderate to severe ADHD, and in their twenties, with IQ scores of at least 85.
The use of a liquid formulation enabled doses to be raised very gradually, starting with a daily dose of 5 mg(1mL) and titrating up to 60 mg over the first three weeks, then maintaining that level through the sixth week. Participants were reevaluated for ADHD symptoms every week during the six-week trial. The severity of ASD was assessed at the start, midpoint, and conclusion of the trial, as were other psychiatric symptoms.
Before the trial, researchers agreed on a combination of targets on two clinician-rated scoring systems that would have to be reached for treatment to be considered successful. One is a score of 2 or less on the CGI-S, a measure of illness severity, with scores ranging from 1 (normal, not at all ill) to 7 (most extremely ill). The other is a reduction of at least 30 percent in the AIS RS score, which combines each of 18 symptoms of ADHD on a severity grid (0=not present; 3=severe; overall minimum score: 0; overall maximum score: 54).
After the trial, twelve of the fifteen patients (80 percent) met the preset conditions for success. Fully fourteen (93 percent) saw a ≥ 30 percent reduction in their AISRS score, while twelve scored ≤ 2 on illness severity.
However, when using the patient-rated ASRS scoring system, only five (33 percent) saw a ≥ 30 percent reduction in ADHD severity.
Thirteen participants (87percent) reported at least one adverse event, and nine (60 percent) reported two or more. One reported a serious adverse event (attempted suicide) in a patient with multiple prior attempts. Because the attempt was not deemed due to medication, they continued and completed the trial. Seven participants experienced titration-limiting adverse events (headaches, palpitations, jaw pain, and insomnia). Headache was most frequent (53%), followed by insomnia and anxiety(33% each), and decreased appetite (27%).
During the trial, weight significantly decreased, while pulse significantly increased. There were no significant differences in other vital and cardiovascular measurements.
The authors concluded, "this OLT of short-term MPH-ER therapy documents that acute treatment with MPH-ER in young adults with ASD was associated with significant improvement in ADHD symptoms, mirroring the typically-expected magnitude of response observed in adults with only ADHD. Treatment with MPH-ER was well-tolerated, though associated with a higher than expected frequency of adverse events."
They also cautioned, "The results of this study need to be considered in light of some methodological limitations. This was an open-label study; therefore, assessments were not blind to treatment. We did not employ a placebo control group and, therefore, cannot separate the effects of treatment from time or placebo effects. ... firmer conclusions regarding the safety and efficacy of MPH-ER for the treatment of ADHD in HF-ASD populations await results from larger, randomized, placebo-controlled clinical trials."
Gagan Joshi, Maura DiSalvo, Janet Wozniak, T. AtillaCeranoglu, Amy Yule, Craig Surman, Ronna Fried, Maribel Galdo, BarboraHoskova, Abigail Belser& Joseph Biederman, "A Prospective Open-Label Trial ofLong-Acting Liquid Methylphenidate for the Treatment of attention-deficit/Hyperactivity Disorder in Intellectually Capable Adults with autism spectrum Disorder," The World Journal of Biological Psychiatry (2019)DOI: 10.1080/15622975.2019.1679392.
If you or someone you know has ADHD, you may be familiar with the challenge of staying on medication. Stimulants like methylphenidate (Ritalin) are the most common and effective treatment for ADHD, but a surprisingly large number of people stop taking them within the first year. In our new study, published in Translational Psychiatry, we sought to determine whether a person's genetic makeup plays a role in the development of the disorder.
What We Did
We analyzed data from over 18,000 people with ADHD in Denmark, all of whom had started stimulant medication. We tracked whether they stopped treatment within the first year, defined as going more than six months without filling a prescription. Nearly 4 in 10 (39%) had discontinued by that point. We then looked at their genetic data to see whether DNA differences could help explain who was more likely to stop.
What We Found
The short answer is: genetics does play a role, but it's modest. No single gene had a dramatic effect. Instead, we found that a collection of small genetic influences—distributed across the genome—contributed to the likelihood of stopping treatment early.
One of the most consistent findings was that people with a higher genetic predisposition for psychiatric disorders like schizophrenia, depression, or general mental health difficulties were more likely to discontinue their medication. This was true across all age groups. Interestingly, having a higher genetic risk for ADHD itself was not associated with stopping treatment, suggesting that the genetics of having ADHD and the genetics of staying on medication are quite different things.
We also found that the genetic picture looks different depending on age. In children under 16, body weight genetics (BMI) played a surprising role, children with a genetic tendency toward higher weight were actually less likely to stop, possibly because stimulant-related appetite suppression is less of a problem for them. In older adolescents and adults, higher genetic potential for educational attainment and IQ was linked to staying on treatment, possibly reflecting better access to information and healthcare support.
On the rare variant side, we found a tentative signal that people who stopped treatment had fewer disruptive variants in genes involved in dopamine, the brain chemical that stimulants work on. This might mean that those who continue on medication genuinely have more disruption in their dopamine system and benefit more from stimulant treatment.
What This Means
Our findings suggest that stopping ADHD medication early isn't simply a matter of willpower or forgetting to take a pill. Biology matters. A person's broader genetic vulnerabilities, particularly for other psychiatric disorders, may make it harder to stay on treatment, perhaps because of side effects, poor response, or the complexity of managing multiple mental health challenges at once.
We're still far from being able to use genetics to predict who will stop their medication, the effects we found are real but small, and much of the variation in treatment persistence remains unexplained. But this work is a step toward understanding the biological foundations of treatment challenges in ADHD, and hopefully toward more personalized approaches to care in the future.
Larger studies and research that can distinguish why people stop (side effects versus poor response versus practical barriers), will be the next steps.
ADHD affects both individuals and society in many ways. Children and adolescents with ADHD often struggle with focusing, controlling impulses, and staying organized, which leads to problems with schoolwork, learning, and taking tests. These challenges can cause academic failure and make it harder for them to stay in school.
ADHD symptoms often continue into adulthood, affecting jobs, relationships, and increasing risks for substance abuse and legal problems.
Families of children and adolescents with ADHD face extra stress, with parents more likely to experience depression, anxiety, and relationship difficulties. The economic impact is also large, with billions spent each year on medical care, special education, lost productivity, and other related costs.
Current treatments for ADHD mostly include medication, behavioral therapy, and educational support. While medications like stimulants can help control ADHD symptoms in the short term, they often cause side effects such as loss of appetite, trouble sleeping, slowed growth, cardiovascular risks, and potential substance dependence. These issues can make it hard for children and adolescents to stay on their medication, and about a third either don’t respond well or can’t tolerate the side effects. Once medication is stopped, the benefits fade quickly and do not lead to lasting improvements in executive functions (thinking skills).
Behavioral therapy and parent training can help with behavior problems, but have limited effects on core mental skills like planning and self-control. These approaches also tend to be expensive, require a lot of support from parents and teachers, and are hard to use widely in schools and communities that lack resources.
Recently, exercise interventions have attracted growing interest as a non-pharmacological option. They provide several benefits: no drug-related side effects, easy accessibility, low cost, simple implementation in schools and communities, and enhanced physical and mental health.
Previous meta-analyses examining how exercise interventions affect children and adolescents with ADHD have used traditional univariate models, which treat each study as if it only offers one independent effect size. In contrast, this study used multilevel meta-analysis — a more advanced statistical method modelling both between-study and within-study effects. This approach results in more accurate estimates and more dependable conclusions.
Eligible studies were randomized controlled trials (RCTs) with usual care, no intervention, or waitlist controls, involving children and adolescents aged 5–18 diagnosed with ADHD by internationally recognized diagnostic criteria, and reporting inhibitory control outcomes.
Eleven studies combining 512 children and adolescents met these inclusion standards.
The analysis between experimental and control groups indicated that the exercise intervention group had significantly improved inhibitory control performance compared to the control group, with a medium-to-large effect size. There was very little variation (heterogeneity) in outcome between the studies, and no sign of publication bias.
Within-group analyses showed that experimental groups had significant improvements after the intervention compared to baseline, with large effect sizes and moderate heterogeneity.
By comparison, analyzing control groups over the same period revealed no significant differences, indicating that inhibitory control abilities in these groups remained largely unchanged throughout the observation period. There was little heterogeneity.
Nevertheless, only one of the studies was rated low risk of bias, nine had some concerns, and two were rated high risk of bias. The greatest shortcomings were a lack of blinding and preregistration.
The study authors therefore concluded that the overall evidence quality of this meta-analysis is low, limiting confidence in the results. While exercise interventions seem to improve inhibitory control abilities in children and adolescents with ADHD, significant methodological limitations create uncertainty about the effect size. These require more rigorous future studies to clarify these effects. Despite these caveats, they noted that all included studies reported statistically significant, consistent benefits from exercise interventions, offering preliminary support for their use as an adjunctive approach.
Takeaway
This study lands in the same conversation as the adult ADHD exercise meta-analysis, and together they start to form a coherent picture: exercise appears to support attention and impulse control across the lifespan for people with ADHD, not just in one age group. The honest caveat is that the research quality in this field is still catching up to the enthusiasm — most studies have design weaknesses that limit confidence in the exact size of the effect. But the consistency of findings across studies, age groups, and now two separate meta-analyses is hard to dismiss.
A new study in the respected journal PLOS One analyzes data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) to examine trends in the incidence, prevalence, and disability-adjusted life-years associated with ADHD among adolescents and young adults aged 10 to 24 years between 1990 and 2021.
The GBD 2021, released by the Institute for Health Metrics and Evaluation (U.S.), is a comprehensive global analysis of 371 diseases, injuries, and risk factors – such as ADHD – across 204 countries from 1990 to 2021. Its open-source data are publicly available.
First, a distinction. Incidence measures the number of new cases of a disease that develop in a specific population each year. Prevalence measures the total number of existing cases – both new and pre-existing – in a population each year.
The estimated global incidence of ADHD declined marginally from 12.61 per 100,000 population in 1990 to 11.89 per 100,000 population in 2021, representing an average annual decrease of 0.6% in age-standardized incidence. The rates observed were comparable between males and females.
Regional trends varied: Western Europe had the highest rise in ADHD incidence (0.5% annually), while North Africa and the Middle East saw the largest drop (0.7% annually). Overall, a higher Socio-Demographic Index (SDI) is linked to a greater incidence, although it is far from a perfect fit. Nationally, showed the highest increase in ADHD incidence (1.15% annually), while Qatar showed the largest decrease with an annualized reduction of 1.77%.
The estimated global prevalence of ADHD declined marginally from 2.38% in 1990 to 2.17% in 2021. Again, the decline was similar for males and females, and across all age groups (10-14, 15-19, 20-24). Higher SDI was associated with higher prevalence, but inconsistently.
Disability-adjusted life-years (DALYs) combine years lost from early death and years lived with disability to measure disease burden. Globally, the age-standardized DALYs rate for ADHD decreased slightly from 30.3 per 100,000 population to 26.6 per 100,000 population, for an average annual decline of 0.6%. The decline occurred across age groups and was similar between males and females.
The authors concluded that ADHD rates and related health burdens have generally declined over the past quarter century, though recent patterns are less consistent due to factors like socioeconomic changes and evolving diagnostic standards. Continued research is needed to improve the accuracy and accessibility of ADHD diagnosis and treatment to further reduce its global impact.
Take-Away:
The broader takeaway is one of cautious reassurance. Despite rising public awareness and diagnosis rates in many Western countries, the global picture over 25 years shows a gentle decline in ADHD burden among young people as opposed to a crisis of escalating proportions as social media may make one think. That said, the variation between regions suggests that access to diagnosis, cultural factors, and reporting standards are shaping the numbers as much as underlying biology. Progress is real but uneven, and the work of improving equitable access to diagnosis and care is far from finished.
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