The 2nd of May 1536 is a date that marks the beginning of a historical era, yet for the millions living with attention deficit hyperactivity disorder, the storm has been raging silently within their minds for generations. This neurodevelopmental disorder is not merely a lack of focus or a case of bad behavior; it is a complex interplay of genetic factors and brain maldevelopment that affects executive functioning, the very cognitive processes required to select and monitor behaviors that facilitate the attainment of chosen goals. The core of the disorder lies in reduced size, functional connectivity, and activation of the prefrontal cortex, alongside imbalances in the noradrenergic and dopaminergic systems that mediate these brain regions. While the symptoms of inattention, hyperactivity, and impulsivity are well-known, the underlying reality is a pervasive impairment that extends far beyond the classroom or the office, predisposing individuals to a diminished quality of life and a reduction in life expectancy. The disorder represents the extreme lower end of a continuous dimensional trait of executive functioning, supported by twin, brain imaging, and molecular genetic studies, suggesting that ADHD is not a binary condition but a point on a spectrum where the brain processes information differently. The precise causes remain unknown in most individual cases, yet meta-analyses have shown that the disorder is primarily genetic with a heritability rate of 70 to 80 percent, where risk factors are highly accumulative. Environmental risks are not related to social or familial factors but exert their effects very early in life, in the prenatal or early postnatal period, challenging the long-held belief that parenting styles or family chaos are the root causes of the condition.
The Genetic Blueprint
The 1st of January 2024 marked a significant milestone in the understanding of the genetic architecture of ADHD, as research continued to unravel the complex web of gene variants that contribute to the disorder. ADHD has a high heritability of 74 percent, meaning that 74 percent of the presence of ADHD in the population is due to genetic factors, with the remaining 20 to 30 percent of variance mediated by de-novo mutations and non-shared environmental factors that provide for or produce brain injuries. There is no significant contribution of the rearing family and social environment to the development of the disorder, a finding that has reshaped the narrative from one of parental failure to one of biological predisposition. Multiple gene variants each slightly increase the likelihood of a person having ADHD, making it a polygenic condition that arises through the accumulation of many genetic risks, each having a very small effect. The siblings of children with ADHD are three to four times more likely to develop the disorder than siblings of children without the disorder, highlighting the strong familial link. A common variant of a gene called latrophilin 3 is estimated to be responsible for about 9 percent of cases, and when this variant is present, people are particularly responsive to stimulant medication. The 7 repeat variant of dopamine receptor D4, known as DRD4-7R, causes increased inhibitory effects induced by dopamine and is associated with ADHD, resulting in a wide range of behavioral phenotypes including split attention. The DRD4 gene is both linked to novelty seeking and ADHD, suggesting that the same genetic traits that drive the disorder may have been advantageous in ancestral forager-gatherer environments. Evolutionary theorists view ADHD traits such as novelty seeking, rapid task-switching, and high exploratory drive as possible cognitive specializations that were advantageous in unpredictable environments, but in modern structured settings, these traits may become mismatched, leading to functional impairment. Natural selection has been acting against genetic variants for ADHD over at least 45,000 years, complicating the suggestion that ADHD was adaptive in the human evolutionary past, yet the disorder may remain at a stable rate by the balance of genetic mutations and removal rate across generations.
Common questions
What is the heritability rate of attention deficit hyperactivity disorder?
Attention deficit hyperactivity disorder has a heritability rate of 74 percent, meaning that 74 percent of the presence of the disorder in the population is due to genetic factors. The remaining 20 to 30 percent of variance is mediated by de-novo mutations and non-shared environmental factors that provide for or produce brain injuries. Environmental risks are not related to social or familial factors but exert their effects very early in life, in the prenatal or early postnatal period.
Which brain structures show volume reduction in attention deficit hyperactivity disorder?
Individuals with attention deficit hyperactivity disorder show a general reduction of volume in certain brain structures, with a proportionally greater decrease in the volume in the left-sided prefrontal cortex. The posterior parietal cortex also shows thinning, and subcortical volumes of the accumbens, amygdala, caudate, hippocampus, and putamen appear smaller compared with controls. Functional MRI studies have shown evidence for a higher connectivity between subcortical and cortical regions, such as between the caudate and prefrontal cortex.
How many adults worldwide have persistent attention deficit hyperactivity disorder?
Worldwide, it is estimated that 2.58 percent of adults have persistent attention deficit hyperactivity disorder, where the individual currently meets the criteria and there is evidence of childhood onset. In 2020, this represented 139.84 million adults, while 6.76 percent of adults have symptomatic attention deficit hyperactivity disorder, meaning that they currently meet the criteria regardless of childhood onset. Around 15 percent of children with attention deficit hyperactivity disorder continue to meet full DSM-IV-TR criteria at 25 years of age.
What are the diagnostic criteria for attention deficit hyperactivity disorder according to the DSM-5?
According to the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders, symptoms must be present for six months or more to a degree that is much greater than others of the same age. Those under 17 require at least six symptoms of either inattention or hyperactivity/impulsivity, while those 17 years or older require at least five symptoms. The symptoms must be present in at least two settings and must directly interfere with or reduce quality of functioning, and several symptoms must have been present before age 12.
Which digital therapeutic was approved by the FDA for attention deficit hyperactivity disorder in 2020?
Akili Interactive Labs's video game-based digital therapeutic AKL-T01, marketed as EndeavourRx, became the first game-based therapeutic granted marketing authorization by the FDA for any type of condition in 2020. A pediatric STARS-ADHD randomized, double-blind, parallel-group, controlled trial demonstrated that AKL-T01 significantly improved performance on the Test of Variables of Attention compared to a control group after four weeks of at-home use. A 2023 study in the Journal of the American Academy of Child & Adolescent Psychiatry investigated the efficacy and safety of AKL-T01 in adults with attention deficit hyperactivity disorder.
The 15th of March 2023 brought new insights into the structural differences of the ADHD brain, revealing a general reduction of volume in certain brain structures, with a proportionally greater decrease in the volume in the left-sided prefrontal cortex. The posterior parietal cortex also shows thinning in individuals with ADHD compared to controls, and other brain structures in the prefrontal-striatal-cerebellar and prefrontal-striatal-thalamic circuits have been found to differ between people with and without ADHD. The subcortical volumes of the accumbens, amygdala, caudate, hippocampus, and putamen appear smaller in individuals with ADHD compared with controls, and structural MRI studies have revealed differences in white matter, with marked differences in inter-hemispheric asymmetry between ADHD and typically developing youths. Functional MRI studies have shown evidence for a higher connectivity between subcortical and cortical regions, such as between the caudate and prefrontal cortex, and the degree of hyperconnectivity between these regions correlated with the severity of inattention or hyperactivity. The dopamine and norepinephrine pathways that originate in the ventral tegmental area and locus coeruleus project to diverse regions of the brain and govern a variety of cognitive processes, with the dopamine pathways and norepinephrine pathways which project to the prefrontal cortex and striatum being directly responsible for modulating executive function, motivation, reward perception, and motor function. These pathways are known to play a central role in the pathophysiology of ADHD, and current models involve the mesocorticolimbic dopamine pathway and the locus coeruleus-noradrenergic system. Previously, it had been suggested that the elevated number of dopamine transporters in people with ADHD was part of the pathophysiology, but it appears the elevated numbers may be due to adaptation following exposure to stimulant medication. The disorder arises from a core deficit in executive functions, including attentional control, inhibitory control, and working memory, which are a set of cognitive processes required to successfully select and monitor behaviors that facilitate the attainment of one's chosen goals.
The Hidden Struggle
The 10th of November 2022 highlighted the often-overlooked emotional and social dimensions of ADHD, particularly the phenomenon of rejection sensitive dysphoria, which is estimated to affect a majority of people with ADHD. This symptom, while not a formal diagnosis, is a common experience characterized by the tendency to anxiously expect, readily perceive, and overreact to social rejection, leading to deep anxiety and humiliation at the slightest rebuff. Karen Horney was the first theorist to discuss the phenomenon of rejection sensitivity, suggesting that it is a component of the neurotic personality, and that it is a tendency to feel deep anxiety and humiliation at the slightest rebuff. Simply being made to wait, for example, could be viewed as a rejection and met with extreme anger and hostility. The causes of individual differences in rejection sensitivity are not well understood, but because of the association between rejection sensitivity and neuroticism, there is a likely genetic predisposition. People with ADHD of all ages are more likely to have problems with social skills, such as social interaction and forming and maintaining friendships, and about half of children and adolescents with ADHD experience social rejection by their peers compared to 10 to 15 percent of non-ADHD children and adolescents. Individuals with attention deficits are prone to having difficulty processing verbal and nonverbal language, which can negatively affect social interaction, and they may also drift off during conversations, miss social cues, and have trouble learning social skills. The disorder is also associated with emotional dysregulation or mood lability, which is generally understood to be a common symptom, and relationship difficulties are frequent, with people with ADHD of all ages being more likely to have problems with social skills. The disorder can be difficult to tell apart from other conditions, and ADHD represents the extreme lower end of the continuous dimensional trait of executive functioning and self-regulation, which is supported by twin, brain imaging and molecular genetic studies.
The Diagnostic Maze
The 5th of August 2023 marked a turning point in the diagnostic landscape of ADHD, as the DSM-5 and its text revision DSM-5-TR provided updated criteria that differentiated childhood and adult diagnostic criteria, a marked departure from the DSM-IV, which did not fully take into account the differences in impairments seen in adulthood compared to childhood. ADHD is diagnosed by an assessment of a person's behavioral and mental development, including ruling out the effects of drugs, medications, and other medical or psychiatric problems as explanations for the symptoms, and a diagnosis can be hard to ascertain, as it is hard to distinguish between normal levels of symptoms and levels that cause significant impairment in major life activities. According to the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders, symptoms must be present for six months or more to a degree that is much greater than others of the same age, requiring at least six symptoms of either inattention or hyperactivity/impulsivity for those under 17 and at least five symptoms for those 17 years or older. The symptoms must be present in at least two settings, such as social, school, work, or home, and must directly interfere with or reduce quality of functioning, and additionally, several symptoms must have been present before age 12 as per DSM-5 criteria. However, research indicates the age of onset should not be interpreted as a prerequisite for diagnosis given contextual exceptions, and the diagnosis of ADHD has been criticized as being subjective because it is not based on a biological test. The International Consensus Statement on ADHD concluded that this criticism is unfounded, on the basis that ADHD meets standard criteria for validity of a mental disorder established by Robins and Guze, and the diagnosis is useful for predicting additional problems the patient may have, future patient outcomes, response to treatment, and features that indicate a consistent set of causes for the disorder. The most commonly used rating scales for diagnosing ADHD in children are the Achenbach System of Empirically Based Assessment and include the Child Behavior Checklist used for parents to rate their child's behavior, the Youth Self Report Form used for children to rate their own behavior, and the Teacher Report Form used for teachers to rate their pupil's behavior, and additional rating scales that have been used alone or in combination with other measures to diagnose ADHD include the Behavior Assessment System for Children, Behavior Rating Inventory of Executive Function - Second Edition, and Revised Conners Rating Scale.
The Treatment Landscape
The 20th of September 2021 saw a global scientific consensus that methylphenidate is safe and highly effective for treating ADHD, marking a significant shift in the treatment landscape after years of debate and conflicting reviews. The management of ADHD typically involves counseling or medications, either alone or in combination, and while there are various options of treatment to improve ADHD symptoms, medication therapies substantially improve long-term outcomes, and while eliminating some elevated risks such as obesity, they do come with some risks of adverse events. Medications used include stimulants, atomoxetine, alpha-2 adrenergic receptor agonists, and sometimes antidepressants, and in those who have trouble focusing on long-term rewards, a large amount of positive reinforcement improves task performance. Methylphenidate and amphetamine or its derivatives are often first-line treatments for ADHD, and about 70 percent respond to the first stimulant tried and as few as 10 percent respond to neither amphetamines nor methylphenidate. Stimulants may also reduce the risk of unintentional injuries in children with ADHD, and magnetic resonance imaging studies suggest that long-term treatment with amphetamine or methylphenidate decreases abnormalities in brain structure and function found in subjects with ADHD. A 2018 review found the greatest short-term benefit with methylphenidate in children, and amphetamines in adults, and studies and meta-analyses show that amphetamine is slightly-to-modestly more effective than methylphenidate at reducing symptoms, and they are more effective pharmacotherapy for ADHD than alpha-2-agonists but methylphenidate has comparable efficacy to non-stimulants such as atomoxetine. The likelihood of developing insomnia for ADHD patients taking stimulants has been measured at between 11 and 45 percent for different medications, and may be a main reason for discontinuation, and other side effects, such as tics, decreased appetite and weight loss, or emotional lability, may also lead to discontinuation. Stimulant psychosis and mania are rare at therapeutic doses, appearing to occur in approximately 0.1 percent of individuals, within the first several weeks after starting amphetamine therapy, and the safety of these medications in pregnancy is unclear.
The Adult Reality
The 3rd of December 2022 brought attention to the often-overlooked reality of adult ADHD, as worldwide, it is estimated that 2.58 percent of adults have persistent ADHD, where the individual currently meets the criteria and there is evidence of childhood onset, and 6.76 percent of adults have symptomatic ADHD, meaning that they currently meet the criteria for ADHD, regardless of childhood onset. In 2020, this was 139.84 million and 366.33 million affected adults respectively, and around 15 percent of children with ADHD continue to meet full DSM-IV-TR criteria at 25 years of age, and 50 percent still experience some symptoms, yet most adults remain untreated. Many adults with ADHD without diagnosis and treatment have a disorganized life, and some use non-prescribed drugs or alcohol as a coping mechanism, and other problems may include relationship and job difficulties, and an increased risk of criminal activities. Associated mental health problems include depression, anxiety disorders, and learning disabilities, and some ADHD symptoms in adults differ from those seen in children, as while children with ADHD may climb and run about excessively, adults may experience an inability to relax, or may talk excessively in social situations. Adults with ADHD may start relationships impulsively, display sensation-seeking behavior, and be short-tempered, and addictive behavior such as substance abuse and gambling are common. Previously, changes in ADHD presentation over time led to those diagnosed as children appearing to have outgrown the DSM-IV criteria, and the DSM-5 addresses this issue by differentiating childhood and adult diagnostic criteria, a marked departure from the DSM-IV, which did not fully take into account the differences in impairments seen in adulthood compared to childhood. For diagnosis in an adult, the presence of symptoms since childhood is generally required, and a proportion of adults who meet the criteria for ADHD in adulthood would not have been diagnosed with ADHD as children, and most cases of late-onset ADHD develop the disorder between the ages of 12 and 16 and may therefore be considered early adult or adolescent-onset ADHD.
The Future of Care
The 1st of July 2024 marked a new era in the treatment of ADHD with the approval of digital therapeutics, particularly Akili Interactive Labs's video game-based digital therapeutic AKL-T01, marketed as EndeavourRx, which became the first game-based therapeutic granted marketing authorization by the FDA for any type of condition. Several clinical trials have investigated the efficacy of digital therapeutics, and the pediatric STARS-ADHD randomized, double-blind, parallel-group, controlled trial demonstrated that AKL-T01 significantly improved performance on the Test of Variables of Attention, an objective measure of attention and inhibitory control, compared to a control group after four weeks of at-home use. A subsequent pediatric open-label study, STARS-Adjunct, published in Nature Portfolio's npj Digital Medicine evaluated AKL-T01 as an adjunctive treatment for children with ADHD who were either on stimulant medication or not on stimulant pharmacotherapy, and results showed improvements in ADHD-related impairment and ADHD symptoms after 4 weeks of treatment, with effects persisting during a 4-week pause and further improving with an additional treatment period. Notably, the magnitude of the measured improvement was similar for children both on and off stimulants, and in 2020, AKL-T01 received marketing authorization for pediatric ADHD from the FDA, becoming the first game-based therapeutic granted marketing authorization by the FDA for any type of condition. In addition to pediatric populations, a 2023 study in the Journal of the American Academy of Child & Adolescent Psychiatry investigated the efficacy and safety of AKL-T01 in adults with ADHD, and after six weeks of at-home treatment with AKL-T01, participants showed significant improvements in objective measures of attention, reported ADHD symptoms, and reported quality of life. The magnitude of improvement in attention was nearly seven times greater than that reported in pediatric trials, and the treatment was well-tolerated, with high compliance and no serious adverse events. The management of ADHD typically involves counseling or medications, either alone or in combination, and while there are various options of treatment to improve ADHD symptoms, medication therapies substantially improve long-term outcomes, and while eliminating some elevated risks such as obesity, they do come with some risks of adverse events.