expert analysis from THE ECNP CONGRESS

PARIS (FRONTLINE MEDICAL NEWS) – Huge longitudinal Scandinavian population registries constitute a unique data source that, in recent years, has provided new insights into attention-deficit/hyperactivity disorder and its associated risks of suicidal behavior, accidents, and early mortality, Henrik Larsson, PhD, said at the annual congress of the European College of Neuropsychopharmacology.

“Randomized, controlled trials have provided little information about real-world effectiveness of ADHD medications, such as their potential effects on adverse health outcomes,” said Dr. Larsson of the Karolinska Institute in Stockholm.

He highlighted several key questions about these adverse health outcomes that recently have been addressed by himself and others through the Scandinavian registries: Are individuals with ADHD at increased risk for suicidal behavior, and if so, what explains this risk? Are ADHD patients at elevated risk for early mortality, and does treatment with ADHD medications affect this risk?

Suicidality

Dr. Larsson was senior author of a Swedish national registry study that identified 51,707 patients with ADHD matched by sex and birth year to 258,535 controls. The ADHD patients had significantly higher rates of both attempted and completed suicide.

After adjustment for socioeconomic status, these individuals were at 8.46-fold increased risk for attempted suicide. However, after further adjustment for comorbid psychiatric disorders, this dropped substantially to a 3.62-fold increased risk.

The same pattern pertained to completed suicide: The risk after adjustment for socioeconomic status was increased 12.3-fold in individuals with ADHD, compared with controls, but the risk dropped to 5.91-fold after further adjustment for comorbid psychiatric disorders ( JAMA Psychiatry. 2014 Aug;71[8]:958-64 ).

The clinical take home point: “Detection and treatment of comorbid conditions probably will help reduce suicidal behavior in ADHD,” Dr. Larsson said.

This study also showed that increased familial risk also is a key factor in the increased risk of suicidal behavior in the ADHD population. Parents of individuals with ADHD were at 2.42-fold increased risk of attempted suicide, compared with controls, and full siblings were at 2.28-fold increased risk. In contrast, the risk in half-siblings, while significantly greater than in controls, was lower than in the genetically closer first-degree relatives: Maternal half-siblings were at 1.57-fold increased risk, and paternal half-siblings were at 1.57-fold greater risk. Cousins were at 1.39-fold increased risk.

The same held true for completed suicide risk. And the familial associations remained significant even after excluding relatives with ADHD.

“Regarding the shared familial factors, I’m tempted to hypothesize that this might involve pleiotropic effects reflecting genetic variants associated with impulsivity,” said Dr. Larsson. To further understand the biological mechanisms underlying ADHD and associated adverse health outcomes requires multiple disciplines to work together. For such work, Dr. Larsson collaborates with international colleagues in several consortia.

ADHD medications and suicidality

Concerns regarding this question were raised by a meta-analysis based on clinical trials data that suggested patients’ increased suicidality might be caused by the effects of ADHD medications. But the meta-analysis was seriously flawed by what epidemiologists call confounding by indication, which is the potential for bias to be introduced when a group of patients on medication is compared with another group off medication. The confounding results from the fact that ADHD patients on medication are different from those who aren’t: They are likely to be more symptomatic and have more comorbidities.

To bypass the confounding issue, Dr. Larsson and his coinvestigators turned to the Swedish registries and identified 37,936 patients with ADHD with a total of 7,019 suicide-related events during nearly 151,000 person-years of follow-up. When they compared patients on drug treatment with those who were not, they found – as in the other investigators’ meta-analysis – that drug treatment was associated with a statistically significant 1.31-fold increased risk of suicide-related events. However, when they performed a more appropriate between-individual analysis, Dr. Larsson and his colleagues found that, when patients with ADHD were using stimulant medications, they had a significant 19% lower risk of suicide-related events than when they were off medication. While on nonstimulant ADHD medications, their suicidality risk was no different from when off medication (BMJ. 2014 Jun 18;348:g3769. doi: 10.1136/bmj.g3769 ).

ADHD and early mortality risk

Prior studies have established that ADHD is associated with a proclivity to engage in risk-taking behaviors, including substance abuse, criminality, risky sexual behavior, and accidents, which are themselves associated with early mortality.

Sure enough, when Danish investigators turned to their national registries, identified 32,061 individuals with ADHD born during 1981-2011, and followed them through 2013, they found that, during nearly 25 million person-years of follow-up, the mortality rate was 5.85 deaths per 10,000 person-years in individuals with ADHD, compared with 2.21 deaths per 10,000 person-years in controls, resulting in a fully adjusted mortality rate ratio of 2.07. The rate ratio was 1.86 for ADHD patients under age 6 years, 1.58 in those aged 6-17 years, and 4.25 for patients aged 18 years and older ( Lancet. 2015 May 30;385[9983]:2190-6 ).

Accidents were the most common cause of death. Could ADHD medications modify this risk of fatal accidents?

Serious motor vehicle accidents

Dr. Larsson and his coinvestigators used registry data to follow 17,408 Swedish adults with ADHD for serious transport accidents involving a trip to the emergency room or death during 2006-2009. The risk was increased by an adjusted 1.47-fold in men with ADHD and by 1.45-fold in women with the disorder. However, in the within-individual analysis, men were 58% less likely to have a serious transport accident when they were on ADHD medication than when off medication. There was no statistically significant effect of ADHD medications on the risk in women with ADHD.

The investigators estimated that 41%-49% of transport accidents in men with ADHD could have been avoided had they been on drug therapy continuously throughout the follow-up period ( JAMA Psychiatry. 2014 Mar;71[3]:319-25 ).

Similar results – that is, data showing that being on ADHD medication reduces the elevated risk of serious accidents – have been reported in four other independent studies conducted in Denmark, Germany, Hong Kong, and most recently in a U.S. analysis by Dr. Larsson and coinvestigators of more than 2.3 million patients with ADHD in a U.S. commercial health insurance claims database ( JAMA Psychiatry. 2017 Jun 1;74[6]:597-603 ).

These findings collectively highlight the public health importance of diagnosing and treating ADHD.

But Dr. Larsson wanted his audience to take home another key lesson: “ADHD is a disorder that can be associated with serious outcomes, including suicide and accidents. It’s nevertheless important to remember that the absolute risks here are very low for any of these outcomes, so the majority of individuals with ADHD will never suffer from any of these outcomes. It’s important to keep that in mind.”

Dr. Larsson’s research is funded by the Swedish Research Council, the National Institute of Mental Health, FORTE, Horizon 2020, and Shire.

bjancin@frontlinemedcom.com

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