April 13, 2021
In the world of research, it is unusual for a single study to be definitive. A possible exception is a recent report in the highly esteemedLancet,which concluded that people diagnosed with ADHD were about two times more likely to die early than people without ADHD. The data came from the medical registers of Denmark that include1.92 a million people, of which 32,061 have ADHD. The registers included the times and causes of deaths spanning 32 years.
It is a remarkable resource.We know that people with very severe ADHD are at high risk for substance use disorders and antisocial behaviors. In the Danish study, these disorders also increased the risk for premature death, but the risk was even higher if people with those disorders also had ADHD. ADHD also increased the risk for early death among people without these extra problems. This latter finding points to anADHD-specificpathway to premature death. What is it? Well, we know that ADHD people are at risk for injuries, traffic accidents, and traumatic brain injury. We don’t know for certain why, but two symptom clusters of ADHD, inattention, and impulsivity, would be expected to increase the risk for accidents and injuries. For example, adults who are distracted while driving are clearly at risk for accidents. Accidents accounted for most of the early deaths in the Danish study. But the study also found an increase in natural causes of death due to having ADHD. This may be due to the well-replicated association between ADHD and obesity, or the possibility that ADHD symptoms lead to poor health habits.
In the Danish study, the mean age at diagnosis was 12.3, which means that many of the ADHD people in the study were not treated for many years after the onset of symptoms.The risk for early death increased with the age at diagnosis. This suggests that failing to diagnose and treat ADHD early makes the disorder worse and increases the risk for the types of behaviors that lead to premature death.Will these data change public policy or clinician behavior? I hope so. Perhaps the media will stop trivializing ADHD and accept it as a bona fide disorder in need of early identification and treatment. Policymakers should allocate ADHD people their fair share of healthcare and research resources. For clinicians, early identification and treatment should become the rule rather than the exception.
Talk of premature death will worry parents and patients. That is understandable, but such worries can be alleviated by focusing on two facts: theabsoluterisk for premature death is low, and this risk can be greatly reduced by seeking and adhering to evidence-based treatments for the disorder.
A meta-analysis of eight studies with a combined total of over 396,000 persons with ADHD reported a twofold greater risk of premature death in persons with ADHD as compared with the general population. There was no significant difference in mortality between males and females with ADHD.
But when natural causes of death– primarily disease – were distinguished from unnatural causes, such as injuries and poisoning, virtually all the increased risk was attributable to the latter.
A meta-analysis of four studies with a combined total of over 394,000 participants with ADHD found no significant increase in natural mortality among persons with ADHD. This held for both males and females.
But a meta-analysis of ten studies with over 430,000 persons with ADHD found a nearly threefold increase in unnatural mortality (injuries, poisoning, etc.) in persons with ADHD. Among females (five studies, over 110,000 participants) the increase was threefold. Males with ADHD (five studies, over 310,000 participants) were 2.5 times more susceptible to premature death.
An important caution: in all of these meta-analyses, between-study heterogeneity was extreme, meaning there was little consistency from one study to the next. Moreover, no effort was made to evaluate the likelihood of publication bias.
The largest study, with over 275,000 participants with ADHD, found a negligible and only marginally significant 7% increased all-cause risk of death. It found no increase in natural causes of mortality, but a 50% increase in unnatural causes of premature mortality.
The authors described these results as “suggestive,†but emphasized that “the evidence was judged as only low confidence,†in line with “inconsistent†evidence from previous nationwide population studies: in Denmark, a twofold increase in all-cause mortality; in Sweden, a fourfold increase; but in Taiwan, a tiny 7% increase that was at the limit of statistical significance, once the data was fully adjusted for confounding factors.
That led the authors to suggest “that all relevant potential confounders should be accounted for†in “future studies.â€
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Persons with ADHD have known to have high rates of psychiatric comorbidities. There is also growing evidence of somatic (non-psychiatric) comorbid disorders among youths with ADHD, such as metabolic syndrome (which can lead to type 2 diabetes) and chronic inflammation (such as asthma and allergic rhinitis). Much less is known, however, about comorbid conditions in adults with ADHD.
An international team of researchers looked for indicators of comorbid conditions in a nationwide cohort study using Swedish national registers. The target population was Swedish residents between the ages of 18 and 64 in 2013 and more specifically those who had been prescribed ADHD medication. They identified over 41,000 individuals who met these criteria, including over twenty thousand young adults aged 18-29 years, over sixteen thousand middle-aged adults aged 30-49 years, and over four thousand older adults aged 50-64. The remainder of the overall cohort were used as controls.
Young adults receiving ADHD medications were four times as likely to also be receiving somatic medications, and older adults were seven times as likely. The highest rate of co-medication –roughly five times more frequent than among controls – was for respiratory system medications. The second most common was for alimentary tract and metabolic system medications, with odds over four times higher than for controls. Cardiovascular system medications were the next most common, with odds among young adults receiving ADHD medications over four times those of controls, though reducing with age to being twice as common in older adults with ADHD. Patterns were similar among men and women.
Adults receiving ADHD medications were far more likely to also be receiving other psychotropic medications. Middle-aged adults were 21 times as likely to be dispensed such medications as controls, older adults eighteen times more likely, and younger adults fifteen times more likely.
For young adults prescribed ADHD medications, the most prevalent co-prescriptions were for addictive disorders, which were dispensed at over 26 times the rate for controls. For middle-aged and older adults, on the other hand, the most prevalent co-prescriptions were for antipsychotics, which were likewise dispensed at over 26 times the rate for controls. Results remained consistent for individuals who had an ADHD diagnosis in addition to an ADHD prescription.
In addition, individuals receiving ADHD medications were also on average taking more types of prescriptions, rising from 2.5 classes of medications at age 18 to five classes at age 64. For controls, the equivalent numbers were 0.9 types of medications at age 18, rising to 2.7 at age 64.
Looking at specific somatic medications prescribed, those for respiratory conditions were ones typically prescribed for asthma and allergic reactions, reinforcing a previously known association. Insulin preparations also had high rates of co-prescription, again further confirming the known association with obesity and diabetes.
On the other hand, the most commonly dispensed alimentary tract and metabolic system medications included proton pump inhibitors, typically prescribed for gastric/duodenal ulcers and gastroesophageal reflux disease. Sodium fluoride, prescribed to prevent dental caries, was also prominent. Neither of these is an established association and warrants further exploration.
Turning to psychotropic medications, the most frequent prescriptions were with drugs used to treat addictive disorders and with antipsychotics. Rates of opioid co-prescription were also notably high, a source of concern given the higher proclivity of persons with ADHD to substance use disorders.
A Chinese research team recently conducted a systematic search of the peer-reviewed medical journal literature for studies exploring the association between childhood antibiotic exposure and subsequent diagnosis of ADHD in youths 18 years and younger.
A meta-analysis of six studies with a combined total of over 1.5 million participants found that children exposed to antibiotics were 18% more likely to later be diagnosed with ADHD.
There was absolutely no indication of publication bias. Between-study heterogeneity, on the other hand, was extremely high.
With such large cohorts, one can often tease out whether an association is causal, or due to genetic and familial confounding, by looking at matched close relatives.
Three of the studies, with a combined total of well over half a million participants, also compared matched siblings.
Significantly, the meta-analysis among matched siblings found no association whatsoever between childhood exposure to antibiotics and subsequent ADHD. Between-study heterogeneity was virtually nonexistent.
The team concluded, “Our meta-analysis indicated that early-life antibiotic exposure was associated with a subsequent increased risk of ASD or ADHD. However, such association was not found in the sibling-matched analysis, indicating that genetic and familial confounding factors may largely explain the observed association.â€
