What would you like to find today?

Background:

A previous meta-analysis found that children born to mothers with diabetes had a 34% higher risk of developing ADHD compared to those born to non-diabetic mothers.  

However, previous studies suffered methodological limitations, such as small sample sizes, case-control or cross-sectional designs, and insufficient adjustment for key confounders such as maternal socio-economic status, mental health conditions, obesity, and substance use disorders.  

Moreover, many studies relied on self-reported maternal diabetes, and on non-clinical ADHD assessments, such as parental reports or screening tools, which are prone to bias and inaccuracies.  

Furthermore, the role of maternal antidiabetic medication use in relation to ADHD risk has rarely been examined. Antidiabetic medications are effective in controlling high blood sugar during pregnancy, but many can cross the placenta and the blood-brain barrier, raising concerns about potential effects on fetal brain development.  

Study:

To address these gaps, an Australian study team used a large cohort of linked health administrative data from New South Wales to investigate both the association between maternal diabetes and the risk of ADHD and the independent effect of prenatal exposure to antidiabetic medications. 

The study encompassed all mother-child pairs born from 2003 through 2005, with follow-up conducted through 2018 to monitor hospital admissions related to ADHD. That yielded a final cohort of almost 230,000 mother-child pairs. 

The team adjusted for potential confounders including maternal age, socioeconomic status, previous children, pregnancy-related hypertension, caesarean delivery, birth order and plurality, maternal anxiety, depression, schizophrenia, bipolar disorder, substance use (alcohol, tobacco, stimulants, opioids, cannabis), and child factors such as Apgar score, sex, prematurity, and low birth weight. 

Results:

For maternal diabetes overall, there was no significant association with offspring ADHD. That was also true when broken down into pre-existing maternal diabetes and gestational (pregnancy-induced) diabetes.  

In a subset of 11,668 mother-child pairs, including 3,210 involving exposure to antidiabetic medications, there was likewise no significant association with offspring ADHD. 

Conclusion:

The team concluded, “Our findings did not support the hypothesis that maternal diabetes increases the risk of ADHD in children. Additionally, maternal use of antidiabetic medication was not associated with ADHD.” 

This study highlights the importance of high-quality research. A previous meta-analysis linking ADHD and maternal diabetes did not appropriately adjust for confounders and cited many small studies that may have included biased self-report scales. This large, registry-based cohort study of nearly 230,000 mother–child pairs found no evidence that maternal diabetes—whether pre-existing or gestational—or prenatal exposure to antidiabetic medications was associated with subsequent offspring ADHD as measured by hospital-recorded ADHD outcomes. The study’s strengths include its population scale, prolonged follow-up, and extensive adjustment for maternal and perinatal confounders (including maternal mental health and substance-use disorders), which address many limitations of earlier, smaller studies that reported elevated risks.  

‍

Background: 

The COVID-19 pandemic brought environmental changes that may have influenced ADHD symptoms and contributed to higher diagnosis rates. School closures, the transition to remote learning, and restrictions on outdoor activities led to increased screen time and isolation, both of which can affect attention and behavioral regulation. Children and adolescents, who usually depend on social interactions and structured routines, experienced significant disruptions during this period.  

Method:

South Korea has a nationwide single-payer health insurance system that keeps detailed health records on virtually its entire population. To explore the impact of COVID-19 on ADHD, a Korean research team used a database established by the Korean government that tracked all patients with COVID-19 between 2020 and 2023, nationwide COVID vaccination records, and insurance claims. They included all participants aged 6 through 29 years old. 

The onset of ADHD was determined by diagnosis combined with the prescription of ADHD medication. 

Altogether, the study encompassed almost 1.2 million Koreans, including over 150,000 children (6-12), more than 220,000 adolescents (13-19), and almost 800,000 young adults (20-29). 

The team adjusted for age, sex, income, Charlson Comorbidity Index, and medical visits. The Charlson Comorbidity Index predicts the mortality for a patient who may have a range of 17 concurrent conditions, such as heart disease, AIDS, or cancer. 

Results:

With these adjustments, young adults known to be infected with COVID-19 were about 40% more likely to be subsequently diagnosed with ADHD than their counterparts with no record of such infection. 

Adolescents known to be infected with COVID-19 were about twice as likely to be subsequently diagnosed with ADHD than their counterparts with no record of such infection. 

Children known to be infected with COVID-19 were 2.4 times as likely to be subsequently diagnosed with ADHD than their counterparts with no record of such infection. 

All these results were highly significant, and point to much greater impact on the youngest persons infected. 

Interpretation: 

The team concluded, “our nationwide study revealed that the COVID-19 pandemic significantly influenced ADHD incidence (raising incidence between 2020 and 2023), with SARS-CoV-2 infection identified as a critical risk factor,” and “In particular, early intervention and neurological evaluations are needed for children, adolescents, and young adults with a history of SARS-CoV-2 infection.” 

‍

Background: 

Children with ADHD often experience deficits in cognitive processes called executive functions. One of the main executive functions is working memory, which is crucial for learning and problem-solving. Issues related to working memory can impact not just academic performance, but also self-esteem, social interactions, and future career prospects. Daily challenges can include completing homework, remembering tasks, and maintaining focus in class, further complicating the learning and social experiences of those with ADHD. 

Physical activity boosts blood flow to the brain. It also assists neural plasticity, meaning it enables networks of nerve cells to reorganize their connections and grow new connections. That helps improve physical skills and potentially academic performance. It is an engaging, easy-to-implement intervention that effectively and sustainably increases children’s participation, overcoming many limitations of other methods. 

Study: 

A Chinese study team set out to perform a systematic search of the published peer-reviewed medical literature to conduct a meta-analysis focusing specifically on the efficacy of physical activity for boosting working memory. 

The inclusion criteria were fourfold. Studies had to: 

• Provide data specific to children and adolescents 18 years old and under. 

• Rely on clinical diagnoses of ADHD. 

• Involve interventions consisting of physical activity or exercise, including but not limited to aerobic exercise, resistance training, and team sports. 

• Have a minimum duration of five weeks. 

• Be randomized controlled trials (RCTs) or controlled non-randomized experimental studies. 

Eleven studies with a combined total of 588 participants met the inclusion criteria. Five were rated high quality. None were rated low quality. 

Results:

Meta-analysis of these eleven studies yielded a medium effect size improvement in working memory. Variability in study outcomes was acceptable (low heterogeneity). There was no indication of publication bias. 

Combined cognitive and aerobic interventions were associated with more than double the effect size of simple aerobic interventions, reaching large effect size (4 studies, 233 participants). 

Subgroup analysis favored a happy medium, suggesting there are points beyond which more is not better:  

• Hour-long interventions were associated with the greatest improvements, with large effect size (3 studies, 180 participants).  

• Interventions carried out no more than twice a week reached large effect size (3 studies, 130 participants).  

• Total weekly intervention time of no more than 25 hours also reported a large effect size (4 studies, 144 participants).  

Take-Away:

Because this work focuses on working memory, not the symptoms of ADHD, one cannot conclude that physical activity could replace current therapies for ADHD.  It does, however, provide strong evidence that physical activity interventions can meaningfully improve working memory in children with ADHD. The most consistent benefits were seen with structured programs of moderate duration and frequency. As with previous studies, the results seem to suggest that interventions excessively long in duration may have diminishing results, highlighting the importance of optimizing session length, frequency, and total intervention time. Before recommending very specific exercises and durations, however, further study is still needed. Future research should refine protocols and explore mechanisms that maximize effectiveness.

‍

The Background: 

Randomized clinical trials have shown ADHD medications are effective in reducing core ADHD symptoms. Moreover, large observational studies indicate that these medications are associated with lower risks of real-world outcomes, including injuries, crime, transport crashes, suicide attempts, and unnatural-cause mortality. 

Sweden’s ADHD medication use has soared. From 2006 to 2020, children’s use rose almost fivefold, and adults' use more than tenfold. This places Sweden among the highest globally in ADHD prescriptions. 

Research indicates that rising prescription rates are due to changes in diagnostic criteria and their interpretation, parental perception, and greater awareness of ADHD, rather than an actual increase in its prevalence. 

Sweden has a single-payer health insurance system that covers virtually its entire population, as well as a system of national registers that link health care records to other population databases.  

The Study:

A research team based in Sweden used that data to explore how the impact of ADHD medication on self-harm, injuries, traffic crashes, and crime has evolved with the dramatic increase in ADHD prescription rates. The team hypothesized that effects would decrease as medications were prescribed to a broader group of patients, including those with fewer impairments and risky behaviors who might not derive as much benefit from pharmacotherapy. 

The team identified all individuals aged 4 to 64 who were prescribed ADHD medication and living in Sweden in the fifteen years from 2006 through 2020. From this base cohort, they selected four specific cohorts for self-harm, unintentional injury, traffic crashes, and crime, consisting of individuals who experienced at least one relevant event during the study period. 

They used a self-controlled case series (SCCS) design to explore the link between ADHD medication use and outcomes. This approach allows individuals to serve as their own controls, accounting for confounders like genetics, socioeconomic status, or other constant characteristics during follow-up. 

A non-treatment period was defined as a gap of 30 days or more between two consecutive treatment periods. To examine the link between ADHD medication use and outcomes, the team divided follow-up time into consecutive periods for each individual. A new period began after a treatment switch. They estimated incidence rate ratios (IRRs) to compare the outcome event rates during medicated periods with non-medicated periods for the same individual. 

The team examined how ADHD medication outcomes varied with prescription prevalence across three periods: 2006-2010, 2011-2015, and 2016-2020, during which ADHD medication use continuously increased. 

The overall cohort encompassed almost a quarter million ADHD medication users: just over 57,000 for 2006-2010, just over 127,000 for 2011-2015, and slightly over 200,000 for 2016-2020. 

The Results:

ADHD medication use was linked to significantly lower rates of all studied outcomes during the study period. However, as prescription rates increased five to tenfold in the population, the strongest association for reduction in self-harm was observed between 2006 to 2010 (23% reduction in incidence rate) and was slightly reduced (below 20%) in the two more recent periods, though this change was not statistically significant.  

On the other hand, there was a significant decreasing trend in the reduction of incidence rate ratios for unintentional injury, with a 13% reduction in incidence rate in 2006-2010 decreasing over the two more recent periods to half that amount, 7%. For traffic crashes, a 29% reduction in incidence rate significantly diminished by more than half, to 13%. For crime, a 27% reduction in incidence rate from medication use significantly declined to 16%. 

When considering methylphenidate prescriptions only, these effects were partially attenuated for crime. A 28% reduction in the incidence rate for crime in 2006-2010 dropped to 19% in the two most recent periods, but the trend was not statistically significant. Nevertheless, there were no significant differences from the results in the larger cohort in any of the other categories.   

The Interpretation:

These outcomes were consistent with the team’s hypothesis. The researchers concluded, “While ADHD medications are consistently associated with reduced risk of serious real-world outcomes, the magnitude of these associations have decreased over time alongside rising prescription rates. This underscores the importance of continuously evaluating medication use in different patient populations.” 

‍

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.”  

‍

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. 

‍

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. 

‍

The Background on ADHD Treatments, rTMS and tDCS:

Methylphenidate is known as the gold-standard treatment for ADHD, increasing dopamine concentrations and helping to focus. However, these psychostimulants may be less well-tolerated in adults. Adverse effects include decreased appetite, nausea, racing heartbeat, restlessness, nervousness, and insomnia. 

Neurofeedback is a non-pharmaceutical treatment that combines cognitive behavioral therapy techniques like conditioning and positive reinforcement with electroencephalography (EEG) feedback. Electrodes are placed on specific brain areas, guiding patients to regulate their brainwave activity. 

Repetitive transcranial magnetic stimulation (rTMS) uses electromagnetism to induce an electric field by passing a magnetic field through the scalp. Transcranial direct current stimulation (tDCS), on the other hand, directly applies an electric current through the scalp. Both repetitive transcranial magnetic stimulation (rTMS) and tDCS primarily target the outermost layers of neurons, as they are non-invasive methods. Nevertheless, both techniques are believed to affect deeper layers through interconnected neuronal networks.  

The Study:

A French research team conducted a systematic search of the peer-reviewed medical literature to perform a meta-analysis to explore the efficacy of these experimental treatment techniques. 

Eight studies – four using rTMS and another four using tDCS – met the inclusion criteria. Studies had to be randomized controlled trials (RCTs), and had to involve multiple sessions of treatment. Participants had to be adults previously diagnosed with ADHD.  

Outcomes were measured through self-rated scales, neuropsychological tests, and electrophysiological pre-post evaluations. 

Separate meta-analyses of the four tDCS RCTs combining 154 participants and of the four rTMS RCTs encompassing 149 participants likewise reported no significant improvements. In all cases variation in outcomes between studies was moderate, and there were no signs of publication bias. 

The Conclusion on Neuromechanistic Treatments for ADHD:

Meta-analysis of all eight studies with a combined total of 421 participants reported no significant improvements over controls. Narrowing down to studies that used sham controls likewise produced no significant improvements. So, despite the title of this study, these neuromechanistic treatments do not appear to be the future of treatment for adult ADHD.

‍

According to the World Health Organization, suicide is the second leading cause of death among individuals aged 15 to 29 years. 

A European study team recently released findings of the first meta-analysis to explore the association between clinically diagnosed ADHD in children and adolescents and subsequent suicidality.  

The criteria for study inclusion were: 

• Most participants had to be under 18 at baseline. 

• Longitudinal design, meaning that participants were followed over time. 

• Having an ADHD sample diagnosed in childhood that was followed up for suicidal behavior. 

• Having a control group without ADHD that was followed up for suicidal behavior. 

• That ADHD was clinically diagnosed based on DSM-5 criteria. 

• The total number of participants and of those with suicidal behavior in both the ADHD group and the control group during follow-up were reported. 

All selected studies scored at least eight out of 11 points after quality assessment. The most frequent defect was that it was unclear whether suicidal behavior had occurred before study initiation. 

Meta-analysis of all nine included studies, encompassing more than 4.4 million participants, reported more than threefold greater odds of overall suicidal behavior among children and adolescents previously diagnosed with ADHD, as opposed to children and adolescents not previously diagnosed with ADHD. Study outcomes varied significantly (high heterogeneity) but showed no publication bias. 

Breaking this down into subcategories of risk: 

• Two studies combining 521 participants reported roughly fourfold greater odds of suicidal ideation among those previously diagnosed with ADHD, with negligible heterogeneity. 

• Six studies encompassing a total of more than 87,000 children and adolescents reported more than threefold greater odds of suicide attempt among those previously diagnosed with ADHD, with high heterogeneity. 

• Two studies combining more than 2.6 million participants reported a near-quadrupling of the odds of suicide death among those previously diagnosed with ADHD, with negligible heterogeneity. 

‍

The team concluded, “the current systematic review and meta-analysis has confirmed previous findings that there is an elevated risk for suicidal behavior in ADHD patients.” They also note, however, that “this relationship is heterogeneous and complex, with significant differences across ADHD subtypes, age groups, sexes, comorbidities, and social issues, all of which play important roles in the development of suicidal behavior.”

‍

The Newest Non-stimulant Medication for ADHD

Centanafadine, which is currently under investigation as a treatment for ADHD, will be the first triple reuptake inhibitor for the disorder if it is approved by the FDA. It improves norepinephrine, dopamine and serotonin levels. This new medication is not a stimulant, but due to the dopamine component, it has a stimulant-like effect in patients. In adults, two phase 3 trials and a year-long extension have shown sustained benefits and a tolerable safety profile, laying the groundwork for pediatric research.

Based on this study, improvement was already noticeable after the first week and held steady through week 6. The lower dose (164.4 mg) didn’t separate from placebo, reminding us that getting the dose right will be critical. The effect size was smaller than what is seen for stimulants but 50% of patients had excellent outcomes as indicated by reductions in the ADHD-RS of 50% or more.

Side effect patterns look familiar to anyone who prescribes ADHD medications; loss of appetite, nausea and headaches topped the list. About half of teens on the higher dose reported at least one treatment-emergent adverse event, compared with a quarter of those on placebo. Severe reactions were rare but did include isolated liver enzyme spikes, rash, and a few reports of aggression or somnolence. For everyday practice, that translates to routine growth checks, a look at baseline liver function, and clear guidance to families about reporting rashes or mood changes promptly.

The researchers noted that the study had certain limitations, including limited generalizability to adolescents beyond North America, the exclusion of teacher ratings on the ADHD-RS-5 scale and the study’s short duration. They added that future studies should explore long-term treatment outcomes and efficacy compared with other ADHD treatments, as well as its effect on treating ADHD with comorbid conditions.

Why should this matter to clinicians already juggling multiple non-stimulant options for ADHD?

First, speed. Centanafadine separated from placebo within a week. In this regard, it might be closer to stimulants than to the multi-week ramp-up we expect from current non-stimulants. Second, it offers another option when stimulants are contraindicated or poorly tolerated, or when they raise diversion concerns. Its mechanism also makes it intriguing for patients who need both norepinephrine and dopamine coverage but prefer to avoid schedule II drugs. Because it also improves serotonergic transmission, it may be useful for some of ADHD’s comorbidities (see our new article for evidence about serotonin’s role in these disorders).

Keep in mind that centanafadine for ADHD is still investigational, so participation in clinical trials remains the only access route.

‍