The Role of Serotonin in ADHD and Its Many Comorbidities

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.” 

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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.

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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.” 

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