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.

Anthony_Rostain_AIA_15_Bzb6ml.png.jpgFredriksen M, Dahl AA, Martinsen EW, Klungsoyr O, Haavik J, Peleikis DE “Effectiveness of one-year pharmacological treatment of adult attention-deficit/hyperactivity disorder (ADHD): An open-label prospective study of time in treatment, dose, side-effects and comorbidity.” European Neuropsychopharm 2014 24: 1873-1884.

This new study from Norway provides useful information about the long-term drug treatment of adult ADHD. Prior studies are small, of short duration (e.g. 4-10 weeks) or have problems with high dropout rates or selection biases (i.e. patients with comorbid conditions are often excluded). This naturalistic study examined 250 patients treated with ADHD drugs for one year.
The patients had a mean age of 32.6 years, virtually all of whom (98%) had never been previously diagnosed with ADHD, and none of whom had received prior treatment. Diagnoses and assessments of outcomes were conducted with state-of-the-art methods. Exclusion criteria included any major psychiatric disorder considered to be in immediate need of treatment, any medical contraindications to stimulant treatment, prior use of stimulant medication in adulthood, and the presence of autism spectrum disorder or intellectual disability (IQ < 70).

All study subjects received methylphenidate (MPH) as the first-line medication. Doses were flexibly titrated from 5 mg three times daily to 20 mg three times daily in the in the first six weeks, and to a maximum of 40 mg three times daily during the subsequent study period (one year). Extended-release MPH was offered at the 3-month visit and dosage could be decreased if subjects experienced intolerance. If MPH was not tolerated or ineffective, two alternative medications were offered: d-amphetamine (up to 50 mg daily) or atomoxetine (in doses ranging from 25 mg to 120 mg daily). Outcome measures were obtained at 3, 6 and 12 months after the initiation of treatment. In addition, all subjects received psychoeducational supportive counseling at all follow up visits.

At the end of 12 months, 92% of subjects (N=232) completed the study and 70% (N=163) remained on a medication. Of those on medication, 79% were taking MPH, 15% were taking d-amphetamine, and 6% were on atomoxetine. Mean daily dosages of medications prescribed (60 mg, 30 mg and 40 mg respectively) suggests the subjects were adequately treated. Given the small number of subjects on d- amphetamine or atomoxetine, drug-drug comparisons of treatment effects could not be carried out.

Overall, subjects still taking medication at the end of the 12 month study period were significantly more improved with respect to their ADHD symptoms and had better functional outcomes compared to those who either discontinued treatment or were never medicated. Subjects on the highest doses reported the best outcomes, and an inverse relationship was observed between side effects and effectiveness of treatment. Interestingly, the outcomes of those who discontinued were intermediate between those who never started a medication and those who stayed on one. Prominence of side effects was cited as the most likely reason for stopping medication (almost half), and discontinuation of treatment occurred most often during the first six weeks of treatment. Comorbid anxiety and bipolar disorders, non-alcohol substance use disorders and cumulative amounts of side effects were associated with less effectiveness.

This study was well designed, excellently implemented and comprised of a large enough sample to be of significance to practicing clinicians. While its open-label design makes it possible that patients on medication were over-estimating the effectiveness of treatment, the results appear consistent with prior studies of this type. Naturalistic studies of treatment effectiveness can be helpful in validating current clinical practices and in setting reasonable expectations for patients and clinicians regarding likely treatment outcomes.

Anthony_Rostain_AIA_15_Bzb6ml.png.jpgWaxmonsky JG, et al.  “Does Pharmacological Treatment of ADHD in Adults Enhance Parenting Performance? Results of a Double-Blind Randomized Trial.” CNS Drugs (2014) 28:665-677.

This study examines the impact of pharmacologic treatment of parents with ADHD on their parenting performance.  It has long been observed that parental ADHD reduces the efficacy of parenting behaviors and is often associated with higher rates of comorbid problems in their ADHD children (Hinshaw et al, 2000) and with lower response rates to intervention (Sonuga-Barke, et al 2002, Jensen et al, 2007).  One prior study (Chronis-Tuscano et al 2010) examined the effects of OROS methylphenidate treatment of mothers with ADHD on parent-child interactions.   The results showed some reduction in self-reports of inconsistent discipline and use of corporal punishment.  It also found however no significant treatment effects on observed dyadic interactions.

The aim of this investigation was to test the impact of lisdexamfetamine (LDX) on observable parenting behaviors in adults with ADHD using a double-blind randomized design.   The study participants consisted of parents of ADHD children (aged 5 – 12 years old) who met criteria for ADHD themselves as measured by the ADHD Rating Scale with adult prompts (>28) and with at least moderate severity on the Clinical Global Impressions Severity Scale.  Parents with medical or psychiatric conditions that could be worsened by stimulant medication were excluded from the study.   Children were eligible if they met DSM-IV criteria for ADHD along with Oppositional Defiant Disorder or Conduct Disorder, and were excluded if they met criteria for any other mental disorders.

A total of 30 parents (27% male) were enrolled in the study. In the initial open-label three-week LDX trial, subjects were given medication at increasing doses until an optimal dose was determined (either 30, 50 or 70 mg daily).  In Phase I, parents were given either placebo or medication during each of the two weeks and were observed in a structured interaction with their children.  In Phase II, parents were randomly assigned to receive placebo or medication (at optimal dose) for a 30-day period at the end of which they were assessed during another interaction with their children.  

The results of the study revealed that during the parent-child interaction task, parents on LDX versus placebo gave fewer commands, praised their children more, and had children who exhibited lower rates of inappropriate behavior.  There was also a trend seen in fewer verbalizations and more responsiveness to their children in parents taking LDX.  In addition, lower parental ADHD symptoms at the end of the study period were significantly correlated with greater amounts of giving praise, improved children’s behavior, and reduction in commands given by parents.  Side effects reported by subjects in the study were generally mild and well tolerated.

The authors of this paper conclude that LDX helps ADHD parents of children with ADHD to perform better in a structured parent-child interaction task as compared to parents who did not receive LDX.  While this is a small N study, the results imply that LDX, an approved long acting stimulant treatment for ADHD in adults, can be helpful for parents of ADHD children who have ADHD themselves by improving their parent-child interactions.  It suggests that clinicians should encourage these parents to seek adequate treatment for their ADHD symptoms, and that in so doing, there is a greater likelihood they will be better able to manage their children, and that psychosocial interventions like parent behavior training will be more effective helping ADHD children reduce their negative behaviors.

 

References

Chronis-Tuscano AM, Rooney M, Seymour KE, et al (2010).  Effects of maternal stimulant medication on observed parenting in mother-child dyads with attention-deficit/hyperactivity disorder.  J Clin Child Adolesc Psychol 39:581-587.

Hinshaw SP, Owens, EB, Wells KC, et al (2000).  Family process and treatment outcome in the MTA: negative/ineffective parenting practices in relation to multimodal treatment.  J Abnorm Child Psychol 28:555-568.  

Jensen PS, Arnold LE, Swanson JM, et al (2007).  Three-year follow up of the NIMH MTA study.  JAACAP 46:989-1002.

Sonuga-Barke EJS, Daley D, Thompson M (2002).  Does maternal ADHD reduce the effectiveness of parent training for preschool children’s ADHD?  JAACAP 41:696-702.

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.

  

References

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_ADHD_in_Adults
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.