Reference: JAMA. 2024 Mar 12;331(10):850-860
Practice Point: Don’t forget to consider the harms of inaction when first doing no harm. Untreated ADHD increases the risk of death two-fold, and medication provides an overall mortality benefit measurable as soon as 2 years after treatment initiation.
EBM Pearl: When randomized trials are not feasible (often due to cost, size, or ethical concerns), investigators may use the target trial emulation approach to avoid making errors of assumption that could result in erroneous causal conclusions, which are one of the greatest sources of bias in observational studies. This two-step process involves articulating a causal question by designing a hypothetical ideal trial and then carefully emulating the components of that trial using the available observational data.
Yes, ADHD is both over- and under-diagnosed, and yes, stimulants have abuse potential. But for people who truly suffer from hyperactivity, inattention, and impulsivity, ADHD can be debilitating and even fatal. People with ADHD are twice as likely to die prematurely, mostly due to unnatural causes. A recent study found that medication initiation was associated with a significant reduction in all-cause mortality and particularly death due to unnatural causes among people with ADHD in the first 2-5 years after starting treatment.
Registry data from 148,578 patients 6-64 years old (median age 17, 59% male) living in Sweden with ADHD diagnosis but without treatment in the eighteen months prior to the study period were evaluated in cohorts of treatment initiation or non-initiation. All patients had neuropsych testing, which is required for ADHD diagnosis in Sweden. 57% were started on a medication (most often a stimulant) during the study period. The primary outcomes were all-cause and cause-specific mortality at 2 years, with a sensitivity analysis extending outcomes to 5 years. Cause-specific mortality was divided into “unnatural” (including suicide, accidental poisoning, accidental injuries, and other external injuries) and “natural” (such as a heart attack or cancer). Notably, the authors designed a target trial protocol and adjusted for baseline confounders in an attempt to emulate randomization and reduce bias.
At 2 years, 632 people (0.43%) had died, and by 5 years 1,402 (0.94%) had died, with 67% of all deaths occurring from unnatural causes. The incidence rate of all-cause mortality at 2 years comparing treated vs untreated patients was 39 vs 48 per 10,000 individuals (HR 0.79, 95% CI 0.70-0.88). Further, the 2-year incidence rate of death due to unnatural causes was 26 vs 33 per 10,000 individuals (HR 0.75, 95% CI 0.66-0.86), but there was no significant reduction in death from natural causes. When data were extended to 5 years in a sensitivity analysis, the reduction in all-cause mortality risk was less pronounced and no longer significant, but the reduction in death due to unnatural causes remained significantly reduced (HR 0.89, 95% CI, 0.81-0.97). Subgroup analyses stratified by age (6-24 and 25-64) showed similar results.
We often worry about the potential harms of prescribing stimulant medications, particularly cardiovascular risk and the potential for abuse or diversion, but we might be underestimating the risk of inaction when it comes to treating ADHD. The act of doing something (prescribing medication) naturally lends itself more to thinking about harms than does inaction, but the risk of high blood pressure or even a heart attack in twenty years is a moot point for the people with ADHD who die prematurely. So while we are valiantly considering all-cause mortality, we should think of the all-cause harms too, which includes the harms of action as well as inaction. According to this study, the balance seems to clearly lie in favor of pharmacologic treatment for ADHD.
For more information, see the topic Attention Deficit Hyperactivity Disorder (ADHD) in Adults in DynaMed.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Katharine DeGeorge, MD, MS, Senior Deputy Editor at DynaMed and Associate Professor of Family Medicine at the University of Virginia. Edited by Alan Ehrlich, MD, FAAFP, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School; Dan Randall, MD, MPH, FACP, Deputy Editor at DynaMed; Nicole Jensen, MD, Family Physician at WholeHealth Medical; Vincent Lemaitre, PhD, Medical Editor at DynaMed; Hannah Ekeh, MA, Senior Associate Editor at DynaMed; and Jennifer Wallace, BA, Senior Associate Editor at DynaMed.