Lenard Adler, MD ADHD in AdultsADHD 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.

Anthony_Rostain_AIA_15_Bzb6ml.png.jpgO’Callaghan, P.  “Adherence to stimulants in adult ADHD.”  J Atten Def Hyp Disord. (2014) 6:111-120.

This study uses a mixed-method design to investigate the factors that influence stimulant medication adherence in adults with ADHD.  The author notes that adherence rates for pharmacotherapy in adults with ADHD is reported to be less than 12% which is a significant concern for clinicians treating this population.  Stimulants have been shown to be highly effective in adults with ADHD with more than 70% experiencing a positive response, and with effect sizes in the range of 0.8-0.9 (Faraone, et al, 2006).  Despite these impressive results, less than 50% of adult patients prescribed a stimulant medication are taking them after 3 months, and by 18 months, only 20% are still receiving treatment (Weisler, et al, 2006).  This study sought to examine the reasons for low adherence using a combination of quantitative and qualitative methods in a sample of 67 adults (67% women) between the age of 19 and 64 years who were recruited from the community.   Subjects were given the Adult ADHD Quality of Life Scale (AAQoL) (Brod et al 2005) and were asked if they were taking stimulant medications daily, as needed or not at all.  Analysis of the total AAQoL and subscale scores showed no significant differences among the three adherence categories, indicating that adherence to medications was NOT correlated with reported quality of life.  

The qualitative phase of the study involved a telephone interview of a subset of 18 adults (61% women) who were queried about their experiences with stimulant medications and about their perceptions of the benefits and adverse effects of taking them.  They were also asked to explain how they made the decision to use or not use stimulants.  The responses were examined using a thematic analysis program that classified the subjects’ answers into five categories of the Health Belief Model (Munro et al 2007): severity of ADHD symptoms, barriers of stimulants, benefits of stimulants, “cues to action” (that is, factors that activate the patient’s readiness to change), and self-efficacy (or confidence in one’s ability to take action).   

The study found that all participants encountered barriers in their experience of taking stimulant medication.  Physical side effects were highly reported by patients with a high AAQoL whereas psychological side effects were reported only by patients with low AAQoL scores.  The positive benefits of stimulants were seen more often in patients with high quality of life yet, severity of ADHD symptoms was not associated with medication adherence.  The most salient “cue to action” found in the study pertained to the quality of the clinician-patient relationship.  The majority of patients with high quality of life had positive experiences with their health providers, whereas those with low quality of life reported frustration and dissatisfaction with their clinicians.  This proved to be the most influential factor in reported ADHD quality of life.  As it turns out, self-efficacy was not a significant theme reported by study participants.  

This article provides insights into the reasons for stimulant medication adherence or non-adherence in adult patients with ADHD.  It finds that the clinician-patient relationship is a strong predictor of ADHD quality of life but NOT of treatment adherence, and that perception of barriers to stimulant treatment is linked to the individual’s quality of life.  Despite the limitations of the study (small sample size, predominance of females in the sample, lack of clear generalizability), it offers a glimpse into the contextual factors that influence treatment adherence and it underscores the critical importance of good communication between clinician and patient so as to promote the best possible outcomes.



Brod M, Perwien A, Adler L, et al (2005).  Conceptualization and assessment of quality of life for adults with attention-deficit/hyperactivity disorder.  Prim Psychiatry 12:58-64.

Faraone S, Biederman J, Mick E (2006).  The age-dependent decline of attention deficit hyperactivity disorder: a meta-analysis of follow-up studies.  Psychol Med 36:159-165.

Munro S, Lewin S, Swart T, Volmink J (2007).  A review of health behavior theories: how useful are these for developing interventions to promote long-term medication adherence for TB and HIV/AIDS?  BMC Pub Health 7:1-6.

Weisler R, Biederman J, Spencer T, et al (2006). Mixed amphetamine salts extended-release in the treatment of adult ADHD: a randomized, controlled trial. CNS Spectr 11:625-639.


Editor’s Note: We interviewed several leading ADHD experts on treating ADHD in primary care and acquired some very interesting insights into how clinicians can learn about and treat ADHD in their practices.

Anthony_L_Rostain_MD_MA_-_ADHD_in_AdultsAnthony Rostain, MD MA: Physicians are often afraid about prescribing stimulant medications because they’re not familiar with the diagnosis of ADHD and they’re not sure whether they’re legitimately correct in prescribing these medications. Let’s start first by examining ADHD as a diagnosis. It is a legitimate diagnosis.

There is a medical procedure for making the diagnosis that includes taking careful history, getting the patient to fill out scales, getting collateral information from important others who understand something about the patient’s behavior. In addition you have to gather developmental history and educational history. You have to be aware of all of the different facets of the patient’s functioning and understand that ADHD is impacting and impairing that individual.

Brendan Montano AIA jZJbzOBrendan Montano MD: With familiarity and use of stimulant medications in ADHD I know I became much more willing and able to use them. Also many pediatricians have no problem with stimulants and I feel that that will also occur when the primary care network begins to treat ADHD more vigorously, diagnose it and treat it. Our pediatric allies had been used to treating ADHD in childhood and they’d been familiarized and become comfortable with the use of stimulant medications. I believe the same thing will occur with our adult primary care providers. Familiarity and seeing the beneficial effect will give comfort to those who treat with stimulant medications. Remembering again there are some non-stimulants that are also quite effective. Now, it is important to be aware of the fact that stimulant medications can be diverted, they can be misused, they can be abused.

Stephen Faraone, PhD:
And that’s a reasonable concern. However, today that concern is mitigated by several factors. First, we have new formulations of stimulants that are much less abusable than the immediate-release Ritalin many of you are used to. Second, there are now FDA-approved non-stimulant alternatives for ADHD. So you really do have a very large toolbox of therapies to use for adultswith ADHD.

Brendan Montano, MD: The more you become familiarized and screen for this illness, the more you become familiarized with treating the illness. So I became comfortable by seeing the beneficial effects and the outcomes which were otherwise not going to occur in my ADHD patients. The lack of training of primary care practitioners has created a shortage of treatment for adults with ADHD. We have methodological studies that prove there are 10 million undiagnosed adults with ADHD in the United States. I think the 10 million people who have this disorder really deserve for us to become familiarized not only with how to diagnose ADHD but how to treat it.

Anthony Rostain, MD: It’s important to keep in mind that if you follow sound clinical practice and document what you’re doing, including how you made the diagnosis of ADHD, that you informed the patient about treatment options and that you gave the patient all kinds of patient education materials to warn them about the danger of misusing the medication, then you’re following standard medical practice and you won’t be in any medical or legal difficulty.