Kevin Antshel, PhD, ADHD in AdultsAccording to statistics released in 2014 by the National Student Clearinghouse Research Center1, nearly 1 in 3 college students will drop out in their first year of college. While there are a variety of possible reasons (e.g., financial, etc.) for this sobering statistic, this finding highlights that transitioning to college can be challenging for a significant proportion of adolescents. For adolescents with ADHD, this transition period can be especially demanding. Adolescents with ADHD often move away from a structured environment (e.g., interventions and accommodations occurring at school, parent involvement, etc.) to the less structured environment of the college campus and greater demands for functional independence (e.g., managing medication without the involvement of parents).

A recently published qualitative study by Schaefer and colleagues2 addresses stimulant medication adherence in college freshmen with ADHD, a part of this transition towards independence. In this study, 10 second-semester college freshmen with ADHD (7 males, 3 females) were interviewed using a semi-structured interview guided by the Health Belief Model (HBM), a theory developed to explain health behavior decision-making3.

Using a Likert scale from 0 (not at all controlled) to 10 (fully controlled), college freshmen with ADHD reported having moderate ADHD control (M = 6.1, SD = 2.7). Using a similar Likert scale from 0 (parents not at all involved) to 10 (parents completely involved), college freshmen with ADHD reported that in high school, parental involvement was moderate (M = 6.8, SD = 3.0) yet in college, parental involvement decreased to low levels (M = 2.8; SD = 3.5). Medication barriers identified by the majority of surveyed college freshmen with ADHD included not feeling like taking the medication, difficulty adhering to a fixed medication schedule, difficulties obtaining a refill on time and that the medication interfered with other activities.

Six different themes (presented here in descending order) emerged from the qualitative interviews and were reported by the majority of the 10 freshmen. The theme that was unanimously raised by all freshmen with ADHD related to volitional non-adherence to stimulants. The reasons for this non-adherence were varied yet could be grouped into inaccurate disease beliefs (“outgrew my ADHD”), perceived lower academic demands (“light academic day and no need to take my stimulant”) and medication side effects. While the authors did not explicitly make this link, volitional non-adherence to daily stimulant medication prescriptions sets the stage for stimulant diversion / misuse. By having “extra” medication available, the possibility of stimulant diversion is increased. Consistent with this notion, a second theme that emerged from the interviews was centered on perceived pressure from peers to share stimulant medications. A third theme that emerged from the interviews was that poor ADHD self management had negative implications for academic performance. A fourth theme was that increased social support was needed. The last two themes related to being ill-equipped for the abrupt transition to independence and reluctance to use non-medication management strategies (e.g., failure to use of Office of Disability Services secondary to stigma).

The authors concluded by offering a number of clinical strategies for improving the transition to college for adolescents with ADHD. While not mentioned in the Schaefer et al. study, others have developed programs tailored towards helping adolescents with ADHD transition from high school to college. For example, the Accessing Campus Connections and Empowering Student Success (ACCESS) program developed by Anastopoulos and colleagues4 includes weekly group therapy and individual mentoring. Group treatment sessions address ADHD knowledge (e.g., including medication knowledge), behavioral strategies (e.g., how to access resources on campus) and cognitive skills (e.g., how think adaptively). ACCESS is currently being tested in a randomized controlled clinical trial study after initial pilot data were encouraging.

By virtue of their college student status, college students with ADHD have had higher academic success during elementary, middle and high school and likely have better coping skills and higher general abilities than individuals with ADHD from the general population. (In support of this view, the average age of ADHD diagnosis for the 10 college freshmen was 15.7 years in the Schaefer et al. qualitative study.) At the same time, college students with ADHD are likely to experience a different set of stressors than young adults with ADHD who are not enrolled in college. In this way, college students with ADHD may represent a distinct category of individuals with ADHD who face a distinct set of challenges. Efforts, like those of Schaefer et al., to understand how best to improve the transition of adolescents with ADHD to college are a clinically important topic.

College students, both with and without ADHD, are in the developmental period of “emerging adulthood,” a period of time between 18-25. Emerging adulthood consists of five dimensions: identity exploration (e.g., trying out different career goals), feeling-in-between adolescence and adulthood, possibilities (e.g., setting optimistic life goals), self-focus (e.g., becoming independent from parents), and instability (e.g., uncertainty and stress from exploring life options)5. The Schaefer et al. study did not use emerging adulthood as a framework for understanding the qualitative interview responses from the freshmen with ADHD. However, several of the emerging adulthood dimensions can be observed in the identified themes and individual freshmen responses.

In sum, the Schaefer et al. study provides meaningful information about stimulant medication adherence, an important aspect of the transition to college for adolescents with ADHD. In addition to providing useful information about how to best facilitate a smooth transition to college, the Schaefer et al. study also intimates that efforts to improve stimulant medication adherence (and therein lessen stimulant diversion) are sorely needed for college students with ADHD.
 

References
1. Center NSCR. First-Year Persistence Rate of College Students Declines. 2014; http://nscnews.org/first-year-persistence-rate-of-college-students-declines/. Accessed February 20, 2017.
2. Schaefer MR, Rawlinson AR, Wagoner ST, Shapiro SK, Kavookjian J, Gray WN. Adherence to Attention-Deficit/Hyperactivity Disorder Medication During the Transition to College. The Journal of adolescent health : official publication of the Society for Adolescent Medicine. 2017.
3. Cummings KM, Jette AM, Rosenstock IM. Construct validation of the health belief model. Health Educ Monogr. 1978;6(4):394-405.
4. Anastopoulos AD, King K. A Cognitive-Behavior Therapy and Mentoring Program for College Students With ADHD. Cogn Behav Pract. 2015;22:141-151.
5. Arnett JJ. Emerging adulthood. A theory of development from the late teens through the twenties. The American psychologist. 2000;55(5):469-480.

http://medicalwritingtraining.com/The stimulants methylphenidate and amphetamine are well known for their efficacy in treating symptoms of ADHD in both youth and adults. Although these medications have been used for several decade, relatively little is known about the mechanisms of action that lead to their therapeutic effect. New data about mechanism comes from a meta-analysis by Katya Rubia and colleagues. They analyzed 14 functional magnetic resonance imaging (fMRI) data sets comprising 212 youth with ADHD. Each of these data sets assessed the short term effects of stimulants on fMRI assessed brain activations. In the fMRI paradigm, ADHD and control participants are asked to do a neurocognitive task while the activity of their brains is being measured. Dr. Rubia and colleagues analyzed data from fMRI assessments of time discrimination, inhibition and working memory, each of which are known to be deficient in ADHD patients. The meta-analysis found that the most consistent brain activations were seen in a region comprising the right inferior frontal cortex (IFC) and insula, even when the analysis was limited to previously medication naïve patients. The implicated region of the brain is known to mediate cognitive control, time estimation and attention. Dr. Rubia also notes that other studies show that the IFC/Insula is needed for updating information and allocating attention to relevant stimuli. Another region implicate by the meta-analysis was the right putamen, a region that is rich in dopamine transporters. This finding is consistent with the fact that the dopamine transporter is the main target of stimulant medications. What are the potential clinical implication of these findings? As Dr. Rubia and colleagues note, it is possible that the fMRI anomalies they identified could be used as a biomarker for ADHD or a biomarker to select patients who should respond optimally to stimulant medication. Although fMRI cannot be used as a clinical tool at this time, research of this sort is opening up new horizons for how we understand the etiology of ADHD and the mechanisms whereby medications exert their effects.
 

Reference
Rubia, K., Alegria, A. A., Cubillo, A. I., Smith, A. B., Brammer, M. J. & Radua, J. (2014). Effects of stimulants on brain function in attention-deficit/hyperactivity disorder: a systematic review and meta-analysis. Biol Psychiatry 76, 616-28.

Stephen_Faraone_PhD_ADHD_in_Adults
Does Acetaminophen use During Pregnancy Cause ADHD in Offspring?

Many media outlets have reported on a study suggesting that mothers who use acetaminophen during pregnancy may put their unborn child at risk for ADHD.   Given that acetaminophen is used in many over-the-counter pain killers, correctly reporting such information is crucial. 

As usual, rather than relying on one study, looking at the big picture using all available studies is best.  Because it is not possible to examine this issue with a randomized trial, we must rely on naturalistic studies.  

One registry study (http://www.ncbi.nlm.nih.gov/pubmed/24566677) reported that fetal exposure to acetaminophen predicted an increased risk of ADHD with a risk ratio of 1.37.  The risk was dose-dependent in the sense that it increased with increased maternal use of acetaminophen.  Of particular note, the authors made sure that their results were not accounted for by potential confounds (e.g., maternal fever, inflammation and infection). 

Similar results were reported by another group, which also showed that risk for ADHD was not predicted by maternal use of aspirin, antacids, or antibiotics.  But that study only found an increased risk at age 7 (risk ratio = 2.0) not at age 11. (http://www.ncbi.nlm.nih.gov/pubmed/25251831)

In a Spanish study, (http://www.ncbi.nlm.nih.gov/pubmed/27353198), children exposed prenatally to acetaminophen were more likely to show symptoms of hyperactivity and impulsivity later in life.  The risk ratio was small (1.1) but it increased with the frequency of prenatal acetaminophen use by their mothers. 

We can draw a few conclusions from these studies.  There does seem to be a weak, yet real, association between maternal use of acetaminophen while pregnant and subsequent ADHD or ADHD symptoms in the exposed child.  The association is weak in several ways: there are not many studies, they are all naturalistic and the risk ratios are small.  

So mothers that have used acetaminophen during pregnancy and have an ADHD child should not conclude that their acetaminophen use caused their child’s ADHD.  On the other hand, pregnant women who are considering the use of acetaminophen for fever or pain should discuss other options with their physician.  As with many medical decisions, one must balance competing risks to make an informed decision.

 

http://medicalwritingtraining.com/Many media outlets have reported on a study suggesting that mothers who use acetaminophen during pregnancy may put their unborn child at risk for ADHD. Given that acetaminophen is used in many over-the-counter pain killers, correctly reporting such information is crucial. As usual, rather than relying on one study, looking at the big picture using all available studies is best. Because it is not possible to examine this issue with a randomized trial, we must rely on naturalistic studies.

One registry study (http://www.ncbi.nlm.nih.gov/pubmed/24566677) reported that fetal exposure to acetaminophen predicted an increased risk of ADHD with a risk ratio of 1.37. The risk was dose-dependent in the sense that it increased with increased maternal use of acetaminophen. Of particular note, the authors made sure that their results were not accounted for by potential confounds (e.g., maternal fever, inflammation and infection).

Similar results were reported by another group (http://www.ncbi.nlm.nih.gov/pubmed/25251831), which also showed that risk for ADHD was not predicted by maternal use of aspirin, antacids, or antibiotics. But that study only found an increased risk at age 7 (risk ratio = 2.0) not at age 11. In a Spanish study, (http://www.ncbi.nlm.nih.gov/pubmed/27353198), children exposed prenatally to acetaminophen were more likely to show symptoms of hyperactivity and impulsivity later in life. The risk ratio was small (1.1) but it increased with the frequency of prenatal acetaminophen use by their mothers.

We can draw a few conclusions from these studies. There does seem to be a weak, yet real, association between maternal use of acetaminophen while pregnant and subsequent ADHD or ADHD symptoms in the exposed child. The association is weak in several ways: there are not many studies, they are all naturalistic and the risk ratios are small.

So mothers that have used acetaminophen during pregnancy and have an ADHD child should not conclude that their acetaminophen use caused their child’s ADHD. On the other hand, pregnant women who are considering the use of acetaminophen for fever or pain should discuss other options with their physician. As with many medical decisions, one must balance competing risks to make an informed decision.

Anthony_L_Rostain_MD_MA_-_ADHD_in_AdultsA Research Review

Psychiatry Research 2016 236:136-141.  DOI: 10.1016/j.psychres.2015.12.017  “Supplementary guanfacine hydrochloride as a treatment of attention deficit hyperactivity disorder in adults: A double blind, placebo-controlled study.” Butterfield ME, Saal J, Young B, Young JI.

Guanfacine hydrochloride is a selective alpha-2A partial agonist that is FDA approved for the treatment of ADHD in children and adolescents (see recent reviews by Faraone et al, 2013; Hirota et al, 2014 and Ruggiero et al 2014).  It can be given alone or in combination with psychostimulant medication as its mechanism of action is complementary to these agents.   Despite growing scientific evidence of its effectiveness for this age group, very little is known about the potential benefits of guanfacine for the treatment of ADHD in adults.

In view of concerns about the importance of finding suitable non-stimulant ADHD medications for this population, the authors carried out a randomized placebo controlled trial of extended release guanfacine (GXR) as supplemental treatment for subjects with a suboptimal response to stimulant-only medication treatment. 

Subjects were recruited from local advertisements and from the clinic practice of the authors in suburban Detroit.  Entry criteria included a current diagnosis of ADHD, current treatment with a stimulant medication, and suboptimal response to this medication as evidenced by a score of > 28 on the Attention Deficit Hyperactivity Disorder Rating Scale (ADHD-RS) or of > 4 on the Clinical Global Impression – Severity (CGI-S) Scale.  Exclusion criteria included having another severe Axis I psychiatric disorder, along with subjects with a history of autism, chemical dependence or psychosis.  Subjects with hypertension or any medical condition that might be exacerbated by the study medication.  A total of 26 subjects in the age range of 19 – 62 years were recruited for the study, of which roughly 50% were women, and 85% were Caucasian.  Subjects were randomly assigned to receive either placebo or incremental doses of GXR ranging from 1 to 6 mg daily on a weekly basis over a 10-week study period. 

Subscribe_Ask_the_Experts_CTA_xqcBwr
The primary outcome measures were the ADHD Rating Scale and the Clinical Global Impression – Severity.  Secondary outcome measures included the Arizona Sexual Experience Questionnaire, the Fatigue Symptom Inventory, the Pittsburgh Sleep Quality Index, the Hamilton Anxiety Inventory and the Hamilton Depression Rating Scale.  Baseline and weekly measures of cardiovascular status were collected throughout the study. 

Contrary to the study authors’ expectations, although subjects in both the placebo and the treatment arms of the study showed significant improvements in both primary and secondary outcome measures, the two groups did not differ from one another.  For instance, the mean ADHD-RS score of the placebo group decreased by 10.92 (from 35.23 to 24.31) and that of the GXR treated group decreased by 11.85 (from 35.92 to 24.08).  The CGI-S score in the placebo group decreased by 1.00 and that of the GXR group by 0.85.  There were no differences between the two groups on measures of tolerability, hemodynamics, sleep, anxiety or depression.  Moreover, no treatment x time x group effects were noted. 

The authors comment that several explanations can account for these findings including a strong placebo effect, a generalized study effect (i.e. participating in a clinical trial itself may be beneficial in and of itself), a “regression to the mean” effect for the placebo group, and a potential bias induced by participating in a clinical trial.   Of note, there were no between group differences seen in fatigue, sleep problems, sexual functioning or in hemodynamic measures – a finding that supports the tolerability and safety of GXR in adult patients. 

While this is a “negative study,” it is helpful in clarifying that GXR can be used safely in combination with stimulant medications, that it does not worsen other psychiatric symptoms (e.g. anxiety, depression) and that it may be a helpful adjunctive treatment for adults with ADHD whose stimulant medication is not sufficiently helpful in reducing their symptoms.  Further research with a larger sample size and with measures taken to minimize the placebo effect are certainly warranted.  In the meantime, clinicians who are considering using GXR can be reassured that it is well tolerated in this population.

 

Faraone SV, McBurnett K, Sallee FR, Steeber J, López FA (2013). Guanfacine extended release: a novel treatment for attention-deficit/hyperactivity disorder in children and adolescents. Clinical Therapeutics Nov;35(11):1778-93. doi: 10.1016/j.clinthera.2013.09.005

Hirota T, Schwartz S, Correll CU (2014). Alpha-2 Agonists for Attention-Deficit/Hyperactivity Disorder in youth: A Systematic Review and Meta-Analysis of Monotherapy and Add-On Trials to Stimulant Therapy. J. Amer.. Acad. Child Adolesc. Psychiatry 53(2):153–173.

Ruggiero S, Clavenna A, Reale L, Capuano A, Rossi F, Bonati M (2014). Guanfacine for attention deficit and hyperactivity disorder in pediatrics: A systematic review and meta-analysis.  European Neuropsychopharmacology 24: 1578-1590.

Anthony_Rostain_AIA_15_Bzb6ml.png.jpgPsychiatry Research 2016 236:136-141. DOI: 10.1016/j.psychres.2015.12.017
“Supplementary guanfacine hydrochloride as a treatment of attention deficit hyperactivity disorder in adults: A double blind, placebo-controlled study.”
Butterfield ME, Saal J, Young B, Young JI.

Guanfacine hydrochloride is a selective alpha-2A partial agonist that is FDA approved for the treatment of ADHD in children and adolescents (see recent reviews by Faraone et al, 2013; Hirota et al, 2014 and Ruggiero et al 2014). It can be given alone or in combination with psychostimulant medication as its mechanism of action is complementary to these agents. Despite growing scientific evidence of its effectiveness for this age group, very little is known about the potential benefits of guanfacine for the treatment of ADHD in adults. In view of concerns about the importance of finding suitable non-stimulant medications for this population, the authors carried out a randomized placebo controlled trial of extended release guanfacine (GXR) as supplemental treatment for subjects with a suboptimal response to stimulant-only medication treatment.
 
Subjects were recruited from local advertisements and from the clinic practice of the authors in suburban Detroit. Entry criteria included a current diagnosis of ADHD, current treatment with a stimulant medication, and suboptimal response to this medication as evidenced by a score of > 28 on the Attention Deficit Hyperactivity Disorder Rating Scale (ADHD-RS) or of > 4 on the Clinical Global Impression – Severity (CGI-S) Scale. Exclusion criteria included having another severe Axis I psychiatric disorder, along with subjects with a history of autism, chemical dependence or psychosis. Subjects with hypertension or any medical condition that might be exacerbated by the study medication. A total of 26 subjects in the age range of 19 – 62 years were recruited for the study, of which roughly 50% were women, and 85% were Caucasian. Subjects were randomly assigned to receive either placebo or incremental doses of GXR ranging from 1 to 6 mg daily on a weekly basis over a 10-week study period.
 
The primary outcome measures were the ADHD Rating Scale and the Clinical Global Impression – Severity. Secondary outcome measures included the Arizona Sexual Experience Questionnaire, the Fatigue Symptom Inventory, the Pittsburgh Sleep Quality Index, the Hamilton Anxiety Inventory and the Hamilton Depression Rating Scale. Baseline and weekly measures of cardiovascular status were collected throughout the study.
 
Contrary to the study authors’ expectations, although subjects in both the placebo and the treatment arms of the study showed significant improvements in both primary and secondary outcome measures, the two groups did not differ from one another. For instance, the mean ADHD-RS score of the placebo group decreased by 10.92 (from 35.23 to 24.31) and that of the GXR treated group decreased by 11.85 (from 35.92 to 24.08). The CGI-S score in the placebo group decreased by 1.00 and that of the GXR group by 0.85. There were no differences between the two groups on measures of tolerability, hemodynamics, sleep, anxiety or depression. Moreover, no treatment x time x group effects were noted.

The authors comment that several explanations can account for these findings including a strong placebo effect, a generalized study effect (i.e. participating in a clinical trial itself may be beneficial in and of itself), a “regression to the mean” effect for the placebo group, and a potential bias induced by participating in a clinical trial. Of note, there were no between group differences seen in fatigue, sleep problems, sexual functioning or in hemodynamic measures – a finding that supports the tolerability and safety of GXR in adult patients.

While this is a “negative study,” it is helpful in clarifying that GXR can be used safely in combination with stimulant medications, that it does not worsen other psychiatric symptoms (e.g. anxiety, depression) and that it may be a helpful adjunctive treatment for adults with ADHD whose stimulant medication is not sufficiently helpful in reducing their symptoms. Further research with a larger sample size and with measures taken to minimize the placebo effect are certainly warranted. In the meantime, clinicians who are considering using GXR can be reassured that it is well tolerated in this population.

 
Faraone SV, McBurnett K, Sallee FR, Steeber J, López FA (2013). Guanfacine extended release: a novel treatment for attention-deficit/hyperactivity disorder in children and adolescents. Clinical Therapeutics Nov;35(11):1778-93. doi: 10.1016/j.clinthera.2013.09.005
Hirota T, Schwartz S, Correll CU (2014). Alpha-2 Agonists for Attention-Deficit/Hyperactivity Disorder in youth: A Systematic Review and Meta-Analysis of Monotherapy and Add-On Trials to Stimulant Therapy. J. Amer.. Acad. Child Adolesc. Psychiatry 53(2):153–173.
Ruggiero S, Clavenna A, Reale L, Capuano A, Rossi F, Bonati M (2014). Guanfacine for attention deficit and hyperactivity disorder in pediatrics: A systematic review and meta-analysis. European Neuropsychopharmacology 24: 1578-1590.

Lenard Adler, MD ADHD in AdultsKabul,S; Alatorre,C; Montejano,LB; Farr,AM; Clemow, DB.

CNS Neuroscience & Therapeutics 21 (2015) 936–942.

This study describes a large prescription database survey of dosing patterns of atmoxetine, between January 2006 and December 2001, in adults with ADHD. 12,412 adults >= 18 y.o. met inclusion criteria of: 1) having at least one claim coded for ADHD, 2) having continuous medical and prescription benefits for the 6 months prior and 12 after the index (initial atomoxetine prescription) and 3) having been treated with atomoxetine monotherapy. The survey examined dosing patterns and the average daily dose of atomoxetine prescribed in the 31 to 365 days following the index prescription of atomoxetine (to allow titration). Adults were divided into four dosing cohorts: 1) suboptimal (average daily dose < 80 mg/day) (n=4548, 36.6%) , recommended (80-100 mg/day) (n=3323, 26.8%) , above-recommended (> 100 mg/day) (n=213, 1.7%) and fluctuating (adults who could not be classified readily into one of the above three cohorts as their dose changed commonly during the treatment period). The fluctuating dose cohort (n=4328, 34.9%) was excluded from subsequent analyses of patient characteristics.

The suboptimal and recommended cohorts were quite similar in patient characteristics, with the exception of a somewhat higher proportion of younger patients (aged 25-44 years) in the recommended vs. the suboptimal group (45.3% vs. 40.6%); the suboptimal group had somewhat higher percentage of females (53.5% vs. 44%) and lower rates of use of ADHD medication prior to the survey period (16.8% vs. 20.0%) versus the recommended dosing cohort. Rates of co-morbid psychiatric disorders were generally the same in these two groups. The overall dose after titration in the three cohorts was 43 mg/day. Slightly greater than 90% of patients discontinued atomoxetine during the one year observation period.

Conclusions drawn from this trial should be tempered by the retrospective, survey based nature of the investigation. Additionally, the assignment of 80 mg/day as the recommended dose is purely based upon the atomoxetine label, whereas the clinical trials examined doses in the 40 to 100 mg/day range. Additionally the four month average treatment period with atomoxetine might have led to an under-estimation of final dosing as a percentage of patients were not titrated to final dosing. However, even with these caveats, there are several important findings for clinicians. Atomoxetine in this claims database seems to be at the lower register of recommended ranges; clinicians should attempt to titrate atomoxetine to optimal dosing based on observed side effects and potential side effects. Adherence to atomoxetine treatment in this claim database was poor, as has been reported in several other studies of ADHD medications in general (stimulants and non-stimulants). Clinicians should make all attempts to improve adherence to medication treatment and attempt to mitigate potential reasons for non-adherence, as patients will only get better if they take their medications.

Anthony_Rostain_AIA_15_Bzb6ml.png.jpgJ Atten Disord. 2014 Jun 26, p.1-11. doi: 1087054714538659.

“Possible Medication-Resistant Deficits in Adult ADHD”

Maruta, J., Spielman, L.A., Tseretopoulos, I.D., Hezghia, A., Ghajar, J.

This article reports on neurocognitive and visual tracking performance of adult subjects with ADHD on and off stimulant medication in an effort to clarify the precise attention impairments seen in this population.  Twenty-three adults with ADHD and forty-six two-for-one matched normal controls were assessed on a variety of neurocognitive and visual tracking measures.  Adult ADHD subjects were tested on and off their prescribed stimulant medication, and results of test performance were compared using paired t test statistical analysis.  Tests included the Attention Network Test (ANT), the Spatial Span subtest of the Wechsler Memory Scale, a circular visual tracking test, and a reaction time test.  None of the ANT metrics or visual tracking tests demonstrated differences between controls and ADHD patients on medication.   However, significant differences were seen in the spatial span tests and in the reaction time tests when they were administered after attention-demanding tasks.  These results suggest that for adults with ADHD, stimulant medications can improve visual tracking, reaction time and alerting and orienting, but they do not seem to improve visual-spatial working memory or susceptibility to cognitive fatigue.   These findings are worthwhile considering when advising patients about the benefits of taking stimulant medication insofar as some aspects of cognitive functioning may not improve as dramatically as others do.

Lenard Adler, MD ADHD in AdultsAtomoxetine and the Treatment of Executive Dysfunction
ADHD 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.jpgProven ADHD Medications for Adults – OROS-methylphenidate

Many studies have documented that ADHD patients have difficulties with the type of complex brain processes neurologists call “Executive Functions” (EF). A 2011 study of ADHD in Adults for example found roughly 40% have executive function deficits (EFDs) (Biederman, et al. 2011). EFs help us organize our lives, manage time, remember complex material and complete complex sequences of behavior. A deficit in executive function is therefore one of the common symptoms of Adult ADHD.
A recent study on medication for ADHD in adults examines the effects of OROS-methylphenidate on executive function deficits (EFDs) (Tannetje I. et al.. “OROS-methylphenidate efficacy on specific executive functioning deficits in adults with ADHD: A randomized, placebo-controlled cross-over study.” European Neuropsychopharma-cology. Available online 17 January 2014, ISSN 0924-977X. http://dx.doi.org/10.1016/j.euroneuro.2014.01.007). The authors used a randomized, placebo-controlled cross-over design to examine the effects of a 72 mg dose of OROS-MPH on 22 subjects’ performance on two versions of the Continuous Performance Test (CPT), a measure of sustained attention and working memory.

Study subjects were stimulant medication-naive. 25% had no Continuous Performance Test (CPT) deficits, 50% had a few CPT deficits, and 25% had multiple deficits, which is consistent with the Biederman study previously noted. Compared with placebo, OROS-MPH improved performance only on reaction time variability (RTV), a measure of sustained attention. High RTV indicates a deficit in information processing and functional integration. Patients with higher EFDs and more severe ADHD symptoms had a better response to medication. Differences in commission errors and discriminative ability between placebo vs OROS-MPH individuals were not noted. In addition, there was a poor relationship between objective and subjective efficacy of the medication.

The findings of this well designed experimental study are interesting in several ways. First, even with a small sample, robust effects of OROS-MPH vs. placebo were seen on Response Time Variability (RTV). In individuals with ADHD, RTV has been shown to be highly responsive to stimulant medication (Kofler, et al, 2012). This study confirms this finding.
Second, this study validates the use of an objective neurocognitive test to measure the responsiveness of adults with ADHD to pharmacologic treatment. An objective test of medication response could help to allay public health concerns about ADHD treatment options and the safety and efficacy of stimulant medications for ADHD symptoms in adults.

Thirdly, the RTV finding is compelling. While there remains a great deal of controversy about the role of EFDs in the etiology of ADHD, it is reasonable to assert that RTV has a great deal of salience to the phenomenology of the disorder, especially in adults. Indeed, trouble maintaining sustained attention is the most common subjective complaint reported by adults with ADHD, and is arguably the most constant neurocognitive impairment seen in this population. Clearly it is not unique to ADHD, but it certainly comprises a core feature of the disorder, and has become a central construct in neuropsychological and neuroimaging research.

The authors are honest in their appraisal of the limitations of the study (most notably the small sample size and the heterogeneity of sample subjects’ performance on the CPT at baseline), and they are very reasonable in recommending that more research be undertaken to document the clinical relevance of using the CPT in patient care, as well as to extend our understanding of the underlying neuropsychology of ADHD.

 

References
Biederman J, Mick E, Fried R, Wilner N, Spencer TJ, Faraone SV (2011). “Are stimulants effective in the treatment of executive function deficits? Results from a randomized double blind study of OROS-methylphenidate in adults with ADHD.” Eur. Neuropsychopharmacol., 21: 508–515.
Kofler MJ, Rapport MD, Sarver DE, Raiker JS, Orban SA, Friedman LM, E.G. Kolomeyer EG (2013). “Reaction time variability in ADHD: a meta-analytic review of 319 studies.” Clin. Psychol. Rev., 33 795–811.
Tamm, L, Narad ME, Antonini TN, O’Brien KM, Hawk Jr. LW, J.N. Epstein JN (2012). “Reaction time variability in ADHD: a review.” Neurotherapeutics: J. Am. Soc. Exp. NeuroTherapeutics, 9: 500–508.