January 10, 2023

Danish population study: Sex chromosome abnormalities increase risk of ADHD

Sex chromosome abnormalities are replication errors that produce an atypical number of sex chromosomes.  Most people have 23 pairs of chromosomes for a total of 46.  One pair is called the sex chromosome pair.  It is either XX (for biological females) or XY (for biological males).  The term 46,XY refers to a typical biological male and the term 46,XX refers to the typical biological female.  

In rare cases a person may have only 45 chromosomes due to having only one sex chromosome, the X chromosome (45,X).  Some people, rarely, have an extra sex chromosome and are designated: 47,XXX, 47,XXY, and 47,XYY.  These rare sex chromosome differences occur in between 0.5 and 1.3 per 1,000 livebirths. 

These differences have physical manifestations. For example, 45,X is associated with shorter height and abnormal development of the ovaries. The other three are associated with greater height. 47,XXX is associated with premature ovarian failure and 47,XXY with low testosterone.

A Danish and U.S. team used data from Denmark’s single-payer universal health insurance system to assess the association of these sex chromosome differences with the prevalence of ADHD.

They performed a case-cohort study. The source population was all 1,657,449 singleton births in Denmark between May 1, 1981, and Dec 31, 2008. The cases consisted of all 93,608 individuals in this population who were diagnosed with any of five psychiatric disorders, including ADHD. These were compared with a cohort consisting of 50,615 individuals randomly selected from the source population.

The combined population prevalence of these four sex chromosome differences was 1.45 per 1,000. 47,XXY was the most common, at 1.23 per 1,000, followed by 47,XYY at .82 per 1,000, then 47,XXX at .66 per 1,000. 45,X was by far the least common, at less than .23 per 1,000.

All four conditions were associated with significantly increased risk of ADHD:

  • 47,XXY roughly doubled the risk. 
  • 47,XXX increased the risk 2.5-fold.
  • 47,XYY more than quadrupled the risk.
  • 45,X more than sextupled the risk.

These data are intriguing because we know there  are sex differences in the prevalence of ADHD but the causes of those differences are unknown.  

Given that ADHD is more common in boys than girls, one would have predicted that having an extra Y chromosome would increase risk for ADHD.  That is the case here but we also see that having an extra X chromosome also increases risk, which means that the impact of sex chromosomes on ADHD is not straightforward.

Xabier Calle Sánchez, Simone Montalbano, Morteza Vaez, Morten Dybdahl Krebs, Jonas Byberg-Grauholm, Preben B Mortensen, Anders D Børglum, David M Hougaard, Merete Nordentoft, Daniel H Geschwind, Alfonso Buil, Andrew J Schork, Wesley K Thompson, Armin Raznahan, Dorte Helenius, Thomas Werge, and Andrés Ingason, “Associations of psychiatric disorders with sex chromosome aneuploidies in the Danish iPSYCH2015 dataset: a case-cohort study,” The Lancet Psychiatry (2023) 10(2):129-138, https://doi.org/10.1016/S2215-0366(23)00004-4.

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Meta-analysis Finds Association Between Childhood Febrile Seizures and Subsequent ADHD

Febrile seizure (FS) is a type of childhood seizure accompanied by a fever. It is not caused by infection in the central nervous system or other triggers of acute seizures. It is the most common form of childhood seizure, with an occurrence of 2% to 5% in all infants and children between 6 months and 5 years old. 

Noting that “To the best of our knowledge, no systematic synthesis of literature has assessed the nature and magnitude of the association between FS and ADHD,” a Korean research team performed a systematic search of the medical literature followed by meta-analysis to explore any such association. 

Meta-analysis of twelve studies with a combined total of more than 950,000 persons found that childhood febrile seizures were associated with 90% greater odds of subsequent ADHD. Correcting for publication bias reduced this slightly to 80% greater odds of subsequent ADHD. 

Limiting the meta-analysis to the subset of four studies with over 33,000 participants that adjusted for known confounders strengthened the association. Children who had febrile seizures had greater than 2.6-fold greater odds of subsequently developing ADHD. There was no sign of publication bias, but there was substantial divergence in individual study outcomes (heterogeneity). 

Further limiting the meta-analysis to two studies with a combined 654 participants in which clinical ADHD diagnoses were made by specialists – the gold standard – produced the exact same outcome. In this case, heterogeneity dropped to zero. 

The team concluded, “Overall, our systematic review and meta-analysis has shown a significant positive association between childhood FS and later occurrence of ADHD. Our findings add to the growing body of evidence questioning the notion that childhood FS are universally benign. In addition, the results highlight the need for longitudinal studies to better understand the association between FS and ADHD.”  

August 26, 2025

Meta-analysis Finds Little Evidence in Support of Game-based Digital Interventions for ADHD

ADHD treatment usually involves a combination of medication and behavioral therapy. However, medication can cause side effects, adherence problems, and resistance from patients or caregivers. 

Numerous systematic reviews and meta-analyses have evaluated the effects of non-pharmacological interventions on ADHD. With little research specifically examining game-based interventions for children and adolescents with ADHD or conducting meta-analyses to quantify their treatment effectiveness, a Korean study team performed a systematic search of the peer-reviewed medical literature to do just that.  

The Study: 

To be included, studies had to be randomized controlled trials (RCTs) that involved children and adolescents diagnosed with ADHD. The team excluded RCTs that included participants with psychiatric conditions other than ADHD.  

Eight studies met these standards. Four had a high risk of bias.  

Meta-analysis of four RCTs with a combined total of 481 participants reported no significant improvements in either working memory or inhibition from game-based digital interventions relative to controls. 

Likewise, meta-analysis of three RCTs encompassing 160 children and adolescents found no significant improvement in shifting tasks relative to controls. 

And meta-analysis of two RCTs combining 131 participants reported no significant gains in initiating, planning, organizing, and monitoring abilities, nor in emotional control

The only positive results were from two RCTs with only 90 total participants that indicated some improvement in visuospatial short-term memory and visuospatial working memory.  

There was no indication of effect size, because the team used mean differences instead of standardized mean differences.  

Conclusion:

The team concluded, “The meta-analysis revealed that game-based interventions significantly improved cognitive functions: (a) visuospatial short-term memory … and (b) visuospatial working memory … However, effects on behavioral aspects such as inhibition and monitoring … were not statistically significant, suggesting limited behavioral improvement following the interventions.” 

Simply put, the current evidence does not support the effectiveness of game-based interventions in improving behavioral symptoms of ADHD in children and adolescents. The only positive results were from two studies with a small combined sample size, which does not qualify as a genuine meta-analysis. All the other meta-analyses performed with larger sample sizes reported no benefits. 

Understanding Teen Health and Well-being in ADHD: A Fresh Perspective from the CDC

Recent research from the Centers for Disease Control and Prevention (CDC) highlights distinct health and social-emotional challenges faced by teens diagnosed with Attention-Deficit/Hyperactivity Disorder (ADHD). This study, published in the Journal of Developmental and Behavioral Pediatrics, offers critical insights directly from the teens themselves, providing a unique view often missed when relying solely on parent or clinical reports. 

Researchers analyzed nationally representative data from July 2021 through December 2022, comparing self-reported experiences of teens aged 12 to 17 with and without ADHD. Approximately 10% of teenagers had an ADHD diagnosis, and the findings reveal specific areas where teens with ADHD face notable difficulties. 

Teenagers with ADHD reported significantly higher rates of bullying victimization and struggles in making friends compared to their peers. Surprisingly, they were less likely to report a lack of peer support, suggesting complexities in how they perceive friendships and social networks. The study underscores the importance of directly engaging teens in assessing their social relationships, rather than solely relying on parental perspectives. 

Sleep difficulties emerged as another critical issue for teens with ADHD. About 80% reported problems like difficulty waking up and irregular wake times, markedly higher than their non-ADHD counterparts. Such disruptions can exacerbate attention difficulties and emotional regulation issues, further complicating daily life for these teens. 

Excessive screen time also stood out, with nearly two-thirds of teens with ADHD spending over four hours daily on screens, excluding schoolwork. This high screen usage is concerning, given its potential negative impact on physical and mental health, including sleep quality and social interactions. 

Notably, the study found no significant differences in physical activity levels or concerns about weight between teens with and without ADHD. This finding contrasts with previous studies that have highlighted lower physical activity among children with ADHD, suggesting the need for continued research on how physical activity is measured and encouraged in this population. 

The study’s authors emphasize the importance of health promotion interventions tailored specifically for teens with ADHD. By directly engaging teens and considering their unique perspectives, interventions can better address social-emotional well-being and healthy lifestyle behaviors, ultimately improving long-term outcomes for this vulnerable group. 

Overall, this research provides compelling evidence for healthcare providers, educators, and families to focus on supporting teens with ADHD in areas of social skills, sleep hygiene, and healthy screen time habits. Such targeted support can significantly enhance the quality of life and health outcomes for adolescents navigating the challenges of ADHD.