DHD Patients with Executive Dysfunction: Atomoxetine vs Placebo Studies

Although they are not included in the formal DSM-5 criteria for adult ADHD, studies have shown that clinically significant executive dysfunction can occur in one-third to one-half of all adults with ADHD. Executive functions are a set of neuropsychological parameters including: 1) working memory, 2) awareness of one’s self in the environment, 3) higher level cognitive functions of prioritization, planning and time estimation/planning and 4) emotional control. Symptoms of ADHD are separate from executive dysfunction and both should be considered in possible treatment design for the particular patient.

There have been two recent reports on the response of executive functions to the non-stimulant atomoxetine used to control ADHD symptoms. (Adler LA, Clemow DB, Williams DW, Durell TM.. Atomoxetine Effects on Executive Function as Measured by the BRIEF-A in Young Adults with ADHD: A Randomized, Double-Blind, Placebo-Controlled Study. PLoS One. 2014 Aug 22;9(8):e104175. doi: 10.1371/journal.pone.0104175. eCollection 2014. and Adler L, Tanaka Y, Williams D, Trzepacz PT, Goto T, Allen AJ, Escobar R, Upadhyaya HP, Executive function in adults with attention-deficit/hyperactivity disorder during treatment with atomoxetine in a randomized, placebo-controlled, withdrawal study. J Clin Psychopharmacol. 2014 Aug;34(4):461-6. doi: 10.1097/JCP.0000000000000138.) Both studies present data on changes in the Behavior Rating Inventory of Executive Function-Adult (BRIEF-A, which is a 75 item, self-report clinical measure of executive function).

The first study presents the changes in BRIEF-A ratings in a study of atomoxetine (40-100 mg/day) versus placebo in young adults with ADHD. Significant effects of atomoxetine vs. placebo were seen on the major indices in the BRIEF, Global Executive Composite (GEC), Behavioral Regulation Index (BRI), and Metacognitive Index (MI), and a number of brief subscales. In other words, the non-stimulant atomoxetine had measureable effects on both ADHD symptoms and executive dysfunction when compared with the administration of a placebo.

The second trial was a randomized, withdrawal study of atomoxetine vs. placebo in patients who previously responded to an open label trial of atomoxetine. Atomoxetine significantly improved the executive function major indices and some subsets compared with placebo, which was maintained for 25 weeks or more. The executive function of patients in the placebo group worsened but did not return to baseline levels after randomization.

In both of these studies the overall effect size on measures of executive dysfunction was less than core ADHD symptoms observed for atomoxetine. Also, the effect on symptoms of emotional control subsets was somewhat less than seen on other subsets. Clinicians should be aware of co-travelling symptoms of executive dysfunction in their adult patients with ADHD and should consider whether to target these symptoms as part of the treatment plan.