Direct Link Between ADHD and Premature Death

Nancy A. Melville

February 26, 2015

Individuals with attention-deficit/hyperactivity disorder (ADHD) are more than twice as likely to die prematurely compared with their counterparts without the disorder, new research shows.

Dr Søren Dalsgaard

The study, which is the first to demonstrate a direct association between ADHD and increased mortality, included nearly 2 million people and had a 32-year follow-up period.

"I did expect to see an increase in mortality with ADHD, but it was a surprise to see the difference was this large, and I think most clinicians will also be surprised by the magnitude of increased mortality," lead author Søren Dalsgaard, MD, PhD, told Medscape Medical News.

The study was published online February 26 in the Lancet.

Mortality Highest in Undiagnosed Adults

According to investigators, many mental disorders are associated with increased mortality. However, little is known about whether this association also applies to ADHD.

For the study, investigators with the National Centre for Register-based Research, at Aarhus University, in Denmark, evaluated data on 1.9 million individuals in Danish national registers from their first birthday through 2013. Among the cohort, 32,061 had been diagnosed with ADHD.

The researchers found a mortality rate of 5.85 per 10,000 person-years among children and adults with ADHD, compared with a rate of 2.21 among those without ADHD.

After adjusting for a range of factors, including age, sex, family history of psychiatric disorders, and employment status, people with ADHD were found to have a mortality rate ratio (MRR) that was more than twice as high as individuals without ADHD (MRR, 2.07; 95% confidence interval [CI], 1.70 - 2.50; P < .0001).

Mortality rates were highest among people diagnosed with ADHD in adulthood, at the age of 18 years or older (MRR, 4.25; 3.05 - 5.78). The risk was lower among children diagnosed at ages younger than 6 years (MRR, 1.86), and it was lowest among those diagnosed from the ages 6 to 17 years (MRR, 1.58).

The authors speculated that the increased mortality risk seen in older age reflects the combined effects of more years of living with the undiagnosed condition.

"This finding could be caused by persistent ADHD being a more severe form of the disorder," they write.

Role of Comorbidities

The presence of antisocial comorbidities associated with ADHD, including oppositional defiant disorder, conduct disorder, and substance use disorder, was associated with as much as an eightfold increased risk for mortality (adjusted MRR, 8.29; 95% CI, 4.85 - 13.09).

However, the increased mortality risk with ADHD remained even after adjusting for those conditions, compared with those without ADHD (MRR, 1.50; 95% CI, 1.11 - 1.98). After the adjustments, the mortality risk was higher among girls and women (MRR, 2.85; 95% CI, 1.56 - 4.71) than in boys and men (MRR 1.27; 95% CI, 0.89 - 1.76), compared with those without ADHD.

The most common causes of death were unnatural causes, particularly accidents.

The authors noted that previous research has shown that people with ADHD tend to be less attentive to potentially severe results of risk-taking behaviors, resulting in the greater risk for injury compared with those without ADHD.

The higher mortality rate among females could be the result of lower rates of diagnosis, largely because males with ADHD tend to be more disruptive in the classroom and are less likely to fall under the radar compared with females, Dr Dalsgaard explained.

"The females diagnosed with ADHD may (due to later diagnosis) represent a subsample with the most severe symptoms and highest impairment, and this may in part explain the gender differences in mortality," he said.

Most Devastating of Outcomes

An important limitation of the study is that it did not evaluate data on people who were treated for ADHD in comparison with those who were not treated. Dr Dalsgaard speculated that the mortality rates would indeed be influenced by treatment.

"We know that treatment reduces the risk of injuries and emergency ward visits in patients with ADHD, and accidents were found to be the most common cause of death in this study, (therefore) we would not be surprised if treatment would have a similar effect on mortality."

Dr Dalsgaard underscored that although clinicians should use caution to keep things in perspective, the findings should send the message that ADHD is, on the other hand, not as benign a disorder as some may believe.

"It is important to reassure patients with ADHD and their families that although ADHD is associated with increased mortality, the absolute risk of death was quite low," he said.

"The mean number of deaths within this cohort across this period of observation, per 10,000 patients with ADHD, was 5.8 individuals per year, compared to 2.2 deaths per year among 10,000 controls."

"(But) our study now documents that ADHD is associated with the most devastating of outcomes, premature death. Hopefully, the findings will result in increased resources for assessment and treatment."

Wake-up Call

In an accompanying commentary published along with the study, Stephen Faraone, MD, of State University of New York Upstate Medical University, in Syracuse, echoed the message that the findings should serve as a wake-up call that failure to identify and treat ADHD can have serious implications.

"For too long, the validity of ADHD as a medical disorder has been challenged," the investigators write. "Policy makers should take heed of these data and allocate a fair share of health care and research resources to people with ADHD."

"For clinicians, early identification and treatment should become the rule rather than the exception."

Lenard Adler, MD, a professor of psychiatry and of child and adolescent psychiatry at the New York University Langone School of Medicine, in New York City, echoed the sentiment.

"(The study) is not surprising because it highlights the significant impairment that comes from ADHD, especially if it is untreated," he told Medscape Medical News.

According to the 2006 National Comorbidity Survey Replication, which Dr Adler coauthored, the prevalence of adult ADHD in the United States was 4.4%, with the majority of cases being undiagnosed.

"Only about 11% of adults with ADHD who had seen a healthcare professional had been diagnosed, so most had been undiagnosed and untreated," he said.

Dr Adler noted that the findings of higher mortality rates in females are consistent with evidence showing that women tend to carry a higher burden with ADHD and get treatment later than males, further underscoring the importance of treatment.

"We do think treatment can lower the risk for impairment associated with ADHD, which also includes higher risks of divorce, lower economic achievement, lower educational achievement, and more substance abuse, and our hope is that we can mitigate these risks by identifying these individuals and getting them appropriate treatment."

The study was supported by a grant from the Lundbeck Foundation. The authors and Dr Dalsgaard have disclosed no relevant financial relationships. Dr Faraone has in the past year received honoraria, travel expenses, or research support from, or has been on advisory boards for, Pfizer, Ironshore, Shire, Akili Interactive Labs, CogCubed, Alcobra, VAYA Pharma, Neurovance, Impax, and NeuroLifeSciences. Dr Faraone's institution is seeking a patent for the use of sodium-hydrogen exchange inhibitors in the treatment of ADHD. Dr Adler has in the past year received research grants and/or been a consultant for Sunovion Pharmaceuticals, Purdue Pharmaceuticals, Enzymotec, Shire Pharmaceuticals, Eli Lilly and Company, APSARD/Pound Foundation, and Lundbeck.

Lancet. Published online February 26, 2015. Abstract

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