Side Effects of Acetaminophen – ADHD?

Stephen V. Faraone, PhD on August 25, 2016

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.

Supplementary GXR for Adult ADHD

Anthony L. Rostain, MD MA on August 18, 2016

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 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.

Non-Stimulant ADHD Medication (Guanfacine) as an Adjunct to ADHD Stimulant Medications

Anthony L. Rostain, MD MA on August 18, 2016

A 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. 


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.

Atomoxetine: Real World Dosing

Lenard A. Adler, on February 4, 2016

Kabul,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.

Medication Resistant Deficits in ADHD

Anthony L. Rostain, MD MA on October 8, 2015

“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.

Atomoxetine, ADHD and Executive Function Deficits

Lenard A. Adler, on April 30, 2015

Atomoxetine 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.

Oros Methylphenidate, ADHD and Executive Function Deficits

Anthony L. Rostain, MD MA on March 12, 2015

Proven 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.

One Year on ADHD Medications

Anthony L. Rostain, MD MA on February 19, 2015

Fredriksen 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.

“Does Pharmacological Treatment of ADHD in Adults Enhance Parenting Performance?”

Anthony L. Rostain, MD MA on January 29, 2015

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.

Atomoxetine and the Treatment of Executive Dysfunction

Lenard A. Adler, on January 23, 2015

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.