Journal Article Annotations
2024, 1st Quarter


Annotations by Julian J. Raffoul, MD, PhD
April, 2024

  1. ADHD Pharmacotherapy and Mortality in Individuals With ADHD.

Of interest:

PUBLICATION #1 — Addiction

ADHD Pharmacotherapy and Mortality in Individuals With ADHD.
Lin Li, Nanbo Zhu, Le Zhang, Ralf Kuja-Halkola, Brian M D’Onofrio, Isabell Brikell, Paul Lichtenstein, Samuele Cortese, Henrik Larsson, Zheng Chang.


The finding:
ADHD, the most prevalent neurodevelopmental condition worldwide, with a prevalence in the U.S. of just under 10% in children and 5% in adults, is associated with a 2-fold increased risk of premature death compared with those without it mainly due to unnatural causes (e.g., suicide, accidental injuries/poisonings, etc.). Pharmacological and non-pharmacological treatment options are available for patients. ADHD medications are effective for reducing core symptoms and epidemiological studies have demonstrated reduced risks of negative outcomes (e.g., injuries, accidents, etc.) which would be expected to reduce mortality rate; however, there are concerns regarding the cardiovascular safety of long-term use of ADHD medications, which could increase mortality rate. This cohort study demonstrated that among approximately 150,000 individuals (aged 6-64 years, median age 17.4 years) diagnosed with ADHD and no prior dispensation of ADHD medication, initiation of treatment within 3 months after diagnosis was significantly associated with lower mortality, in particular for unnatural causes.

Strength and weaknesses:
The study asks whether initiation of ADHD medications (methylphenidate, amphetamine, dexamphetamine, lisdexamfetamine, atomoxetine, and guanfacine) is associated with reduced mortality risk in individuals with ADHD. The main outcomes were all-cause and cause-specific mortality during a 2-year follow-up period. This study boasts numerous strengths including a large, well-powered sample (N = ~ 150,000) across a broad age range (6 to 64 years) enabling the exploration of the association in both children and adults and received an ADHD diagnosis following a thorough neuropsychiatric evaluation. Limitations include the observational nature that cannot conclusively establish causal effects of ADHD medication treatment on mortality risk due to unmeasured confounders, such as lifestyle, could contribute to the associations. ADHD treatment involves more than taking psychotropics and non-medication components may affect treatment outcomes. There is potential for Type I statistical error (false positive) resulting from multiple comparisons regarding cause-specific mortality and subgroup analysis. Lastly, misclassification of exposure or death cannot be ruled out.

The C-L psychiatrist is frequently asked to evaluate and manage patients with symptoms of ADHD, particularly in consult clinics. The elevated mortality risk associated with ADHD and the importance of proper testing and treatment, potentially reducing mortality in patients appropriately treated, is of paramount importance for psychiatrists. Of particular importance are patients with ADHD and co-occurring substance use disorders, a group to whom clinicians may be reluctant to prescribe stimulants. Approximately 8% of the sample in this study had alcohol use disorder and 9% had a non-alcohol substance use disorder; this was considered a covariate in the models for the purposes of this study. Although, the question remains: should medication treatment for ADHD be initiated or deferred when active substance use is present? The study doesn’t answer this question directly, yet the below editorial addresses this and other important questions raised by this study.

PUBLICATION #2 — Addiction

Treating Attention-Deficit/Hyperactivity Disorder Matters.
Frances R Levin, Mariely Hernandez, John J Mariani.

Annotation (unstructured)

This important editorial highlights the strengths and weaknesses of the annotation highlighted above investigating whether ADHD medication, continuously prescribed over the two years following initial diagnosis, was associated with reduced mortality rates compared with those who were not treated with ADHD medication during the same period. Importantly, overarching questions are asked such as how exactly does treating individuals for their ADHD symptoms reduces the risk of unnatural death? Also addressed are valid concerns regarding the misuse or diversion of prescribed stimulant medications, particularly among young adults or individuals who are using other psychoactive substances. Should patients with co-occurring substance use disorders be prescribed stimulants for their ADHD? This is an area of active research interest.