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Cited by 32Attention Deficit Hyperactivity DisorderDevelopmental and Educational NeuropsychologySchizophrenia research and treatment

Atomoxetine Effects on Executive Function as Measured by the BRIEF-A in Young Adults with ADHD: A Randomized, Double-Blind, Placebo-Controlled Study

Open access
Adler, Lenard A., Clemow, David B., Williams, David W., Durell, Todd M.·2014·PLoS ONE
DOI 10.1371/journal.pone.0104175PMC PMC4141744
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Abstract

OBJECTIVE: To evaluate the effect of atomoxetine treatment on executive functions in young adults with attention-deficit/hyperactivity disorder (ADHD). METHODS: In this Phase 4, multi-center, double-blind, placebo-controlled trial, young adults (18-30 years) with ADHD were randomized to receive atomoxetine (20-50 mg BID, N = 220) or placebo (N = 225) for 12 weeks. The Behavior Rating Inventory of Executive Function-Adult (BRIEF-A) consists of 75 self-report items within 9 nonoverlapping clinical scales measuring various aspects of executive functioning. Mean changes from baseline to 12-week endpoint on the BRIEF-A were analyzed using an ANCOVA model (terms: baseline score, treatment, and investigator). RESULTS: At baseline, there were no significant treatment group differences in the percentage of patients with BRIEF-A composite or index T-scores ≥60 (p>.5), with over 92% of patients having composite scores ≥60 (≥60 deemed clinically meaningful for these analyses). At endpoint, statistically significantly greater mean reductions were seen in the atomoxetine versus placebo group for the BRIEF-A Global Executive Composite (GEC), Behavioral Regulation Index (BRI), and Metacognitive Index (MI) scores, as well as the Inhibit, Self-Monitor, Working Memory, Plan/Organize and Task Monitor subscale scores (p<.05), with decreases in scores signifying improvements in executive functioning. Changes in the BRIEF-A Initiate (p = .051), Organization of Materials (p = .051), Shift (p = .090), and Emotional Control (p = .219) subscale scores were not statistically significant. In addition, the validity scales: Inconsistency (p = .644), Infrequency (p = .097), and Negativity (p = .456) were not statistically significant, showing scale validity. CONCLUSION: Statistically significantly greater improvement in executive function was observed in young adults with ADHD in the atomoxetine versus placebo group as measured by changes in the BRIEF-A scales. TRIAL REGISTRATION: ClinicalTrials.gov NCT00510276.

AI snapshot

Written from the paper’s full text.

TL;DR

In a 12-week randomized, double-blind, placebo-controlled trial in young adults with ADHD, atomoxetine produced statistically significantly greater improvement than placebo on several BRIEF-A executive function measures. The largest separation was on the Global Executive Composite, with additional significant effects on the Behavioral Regulation and Metacognitive indices and five of nine subscales.

Key findings

  • Atomoxetine-treated patients had greater mean reductions from baseline to endpoint on BRIEF-A Global Executive Composite (LS mean change −22.4±1.9 vs −14.8±1.9; 95% CI −12.37 to −2.78, p=.002), Behavioral Regulation Index (−7.22±11.77 vs −4.47±10.05, p=.007), and Metacognitive Index (−12.55±15.14 vs −8.93±13.35, p=.003).
  • Statistically significant atomoxetine-versus-placebo improvements were also seen on Inhibit (p=.005), Self-Monitor (p=.005), Working Memory (p<.001), Plan/Organize (p=.010), and Task Monitor (p=.023).
  • Changes were not statistically significant for Initiate (p=.051), Organization of Materials (p=.051), Shift (p=.090), or Emotional Control (p=.219).
  • At baseline, 93.6% of atomoxetine and 92.4% of placebo patients had GEC T-scores ≥60; the GEC treatment effect size was −0.32, described as small to moderate.

Methods

  • Phase 4, multicenter, 12-week, randomized, double-blind, placebo-controlled trial at 32 sites in the United States and Puerto Rico; young adults aged 18–30 with DSM-IV-TR ADHD were randomized 1:1 to atomoxetine (20–50 mg BID, N=220) or placebo (N=225).
  • BRIEF-A analyses included patients with baseline and at least one postbaseline BRIEF-A measurement: atomoxetine N=161 and placebo N=167.
  • Mean changes from baseline to 12-week endpoint were analyzed with a pre-specified ANCOVA model including baseline score, treatment, and investigator; missing data used LOCF, Hochberg’s adjustment controlled multiplicity for component scores, and a post-hoc MMRM sensitivity analysis was performed on GEC.

Limitations

  • The paper states there was an absence of neuropsychological assessments of executive function, limited adjustments for multiple comparisons, no formal informant ADHD ratings, overrepresentation of white participants relative to US demographics, and a higher-than-expected dropout rate that could reduce power.
  • The paper also states BRIEF-A assessments occurred only at baseline, Week 5, and Week 12, and analyses included only patients with both baseline and postbaseline measurements, reducing patient numbers.
  • Evident from the text: executive function was measured only by self-report BRIEF-A, and the GEC effect size was small to moderate (−0.32), so clinical magnitude should be interpreted cautiously.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1371/journal.pone.0104175

Cites

34 of 34 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

4 of 26 cited sources checked · 0 supported · 0 flagged · accuracy not yet measured

  • Findingown data

    There was no statistically significant difference between atomoxetine and placebo in mean change from baseline to last observation on the BRIEF-A Emotional Control subscale (p=.219).

    “Emotional Control | −1.67±4.97 | −1.18±4.48 | .219”
    Quote in the paperNot a substantial claim
  • Findingown data

    Changes from baseline to 12-week endpoint in the BRIEF-A Emotional Control subscale score were not statistically significant (p = .219).

    “Changes in the BRIEF-A Initiate (p = .051), Organization of Materials (p = .051), Shift (p = .090), and Emotional Control (p = .219) subscale scores were not statistically significant.”
    Quote in the paperNot a substantial claim
  • Findingown data

    In young adults with ADHD, atomoxetine produced a greater mean decrease from baseline to last observation in BRIEF-A Global Executive Composite score than placebo (mean change −19.78 vs −13.41, p=.002).

    “Global Executive Composite | −19.78±25.59 | −13.41±21.76 | .002”
    • Also stated in: § Discussion · plain
      “statistically significantly greater mean reductions were observed for the atomoxetine- versus placebo-treated patients for the BRIEF-A Global Executive Composite (GEC)”
    Quote in the paperSubstantial claim
  • Findingown data

    In repeated measures analysis, atomoxetine and placebo groups showed statistically significant separation in BRIEF-A Global Executive Composite change from baseline at Week 5 (difference −7.11, p=.002).

    “5 | Atomoxetine | 157 | −18.02±1.69 | −7.11 | .002 | −11.49 to −2.73”
    • Also stated in: § Results · plain
      “statistically significant separation between the atomoxetine and placebo groups at Week 5 (Visit 4)”
    Quote in the paperSubstantial claim
  • Findingown data

    Atomoxetine treatment produced statistically significantly greater mean reductions from baseline to 12-week endpoint than placebo on the BRIEF-A Metacognitive Index (MI) score.

    “There was a statistically significantly greater decrease in mean change (± standard deviation) from baseline to last observation demonstrated in the atomoxetine group compared with the placebo group not only for the BRIEF-A overall GEC score but also the BRI and MI scores (Table 3).”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 31
  • May combine two claims. 19

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Other stimulant ADHD medications that affect norepinephrine and dopamine levels, such as methylphenidate, have also shown efficacy for improving deficits in some executive functioning categories but not others.

    “Other stimulant ADHD medications that affect norepinephrine and dopamine levels, such as methylphenidate, have also shown efficacy for improving deficits in some executive functioning categories but not others [30], [31].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [30] J Biederman, 2008, Effects of stimulant medication on neuropsychological functioning in young adults with attention-deficit/hyperactivity disorder, J Clin Psychiatry source

      The Results (page not specified) report better sustained attention and verbal learning scores among participants taking stimulants, but not improvements across other measured executive-function domains. The paper studies stimulants as a group; our copy does not establish a methylphenidate-specific effect or discuss norepinephrine and dopamine levels. Its findings therefore support the uneven pattern of improvement, but not those drug-specific details. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [31] J Biederman, 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 source

  • May combine two claims.

    Premisecitation

    Neuropsychological tests have not been shown to reliably predict functional impairment in adult ADHD, while clinical ratings such as the BRIEF have been successful in this regard.

    “neuropsychological tests have not been shown to reliably predict functional impairment in adult ADHD, while clinical ratings such as the BRIEF have been successful in this regard [25], [26].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [25] RA Barkley, 2010, Impairment in occupational functioning and adult ADHD: the predictive utility of executive function (EF) ratings versus EF tests, Arch Clin Neuropsychol source

      The Results and Discussion (page unavailable in our copy) find that executive-function ratings predicted occupational impairment substantially better than executive-function tests in the adults studied. But the study used the Deficits in EF Scale, not the BRIEF, and several tests did predict some occupational outcomes, albeit more weakly; it therefore does not establish the claim for the BRIEF or show that tests never predict impairment. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [26] RA Barkley, 2011, Predicting impairment in major life activities and occupational functioning in hyperactive children as adults: self-reported executive function (EF) deficits versus EF tests, Dev Neuropsychol source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The precise mechanism by which atomoxetine produces its therapeutic effects in ADHD is unknown, but it is thought to be related to selective inhibition of the pre-synaptic norepinephrine transporter, as determined in ex vivo uptake and neurotransmitter depletion studies.

    “The precise mechanism by which atomoxetine produces its therapeutic effects in ADHD is unknown, but it is thought to be related to selective inhibition of the pre-synaptic norepinephrine transporter, as determined in ex vivo uptake and neurotransmitter depletion studies [24].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [24] FP Bymaster, 2002, Atomoxetine increases extracellular levels of norepinephrine and dopamine in the prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder, Neuropsychopharmacol source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Microdialysis studies suggest that atomoxetine may selectively increase dopamine levels in the prefrontal cortex, via the norepinephrine transporter or perhaps via a secondary signaling mechanism.

    “microdialysis studies suggest that atomoxetine may selectively increase dopamine levels in the prefrontal cortex, via the norepinephrine transporter or perhaps via a secondary signaling mechanism [23].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [23] AFT Arnsten, 2011, Catecholamine influences on dorsolateral prefrontal cortical networks, Biol Psychiatry source

      In “NE Mechanisms and ADHD Medications” (page unavailable), the paper says atomoxetine blocks the norepinephrine transporter, which clears dopamine in the PFC, increasing extracellular dopamine and norepinephrine there. It does not describe a secondary signaling mechanism or establish that the dopamine increase is selective to the PFC. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    Mean baseline BRIEF-A validity scores were similar, low, and within the acceptable range for scale validity in both treatment groups.

    “Mean baseline validity scores for both treatment groups were similar, low, and within the acceptable range for scale validity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The BRIEF-A validity scales Inconsistency (p = .644), Infrequency (p = .097), and Negativity (p = .456) did not show statistically significant treatment group differences.

    “In addition, the validity scales: Inconsistency (p = .644), Infrequency (p = .097), and Negativity (p = .456) were not statistically significant, showing scale validity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Mean GEC scores decreased from 155.0±21.5 at baseline to 135.2±28.4 at endpoint in the atomoxetine group (N=161) and from 156.1±21.5 to 142.6±26.6 in the placebo group (N=167).

    “The mean ± standard deviation baseline and end point GEC scores for atomoxetine versus placebo were as follows: 155.0±21.5 to 135.2±28.4 (N = 161) versus 156.1±21.5 to 142.6±26.6 (N = 167).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    The BRIEF-A is a standardized measure consisting of 75 items within 9 nonoverlapping clinical scales that measure various aspects of adult executive functioning and self-regulation in the person's everyday environment.

    “The BRIEF-A is a standardized measure consisting of 75 items within 9 nonoverlapping clinical scales that measure various aspects of adult executive functioning and self-regulation in the person’s everyday environment [19].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] Roth RM, Isquith PK, Gioia GA (2005) Behavior Rating Inventory of Executive Function–Adult Version (BRIEF-A). Lutz, FL: Psychological Assessment Resources. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Amphetamines are believed to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space.

    “Amphetamines are believed to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space [29].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Vyvanse (2012) [package insert]. Wayne, PA: Shire US.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    There was an overrepresentation of white participants relative to African Americans and Hispanics compared with the overall US demographics.

    “There was also an overrepresentation of white participants relative to African Americans and Hispanics compared with the overall US demographics.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    The study was a phase 4, multicenter, 12-week, randomized, placebo-controlled, double-blind trial.

    “This study was a phase 4, multicenter, 12-week, randomized, placebo-controlled, double-blind trial conducted at 32 sites in the United States and Puerto Rico between August 2007 and February 2009.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    The incidence of prior stimulant medication use was approximately 35-38% and similar between treatment groups.

    “The incidence of prior stimulant medication use was approximately 35–38% and similar between treatment groups (Table 1).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Mean changes from baseline to 12-week endpoint on the BRIEF-A were analyzed using a pre-specified ANCOVA model with terms for baseline score, treatment, and investigator.

    “Mean changes from baseline to 12-week endpoint on the BRIEF-A were analyzed using a pre-specified analysis of covariance (ANCOVA) model with terms for baseline score, treatment, and investigator.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    The BRIEF-A yields a Global Executive Composite (GEC), which is a composite of the Behavioral Regulation Index (BRI) and Metacognitive Index (MI); the BRI comprises Inhibit, Shift, Emotional Control, and Self-Monitor subscales, and the MI comprises Initiate, Working Memory, Plan/Organize, Task Monitor, and Organization of Materials subscales.

    “The BRIEF-A yields an overall score, the Global Executive Composite (GEC), which is a composite of 2 index scores: Behavioral Regulation Index (BRI) and Metacognitive Index (MI). The BRI is comprised of 4 subscales (Inhibit, Shift, Emotional Control, and Self-Monitor) and the MI is comprised of 5 subscales (Initiate, Working Memory, Plan/Organize, Task Monitor, and Organization of Materials).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] Roth RM, Isquith PK, Gioia GA (2005) Behavior Rating Inventory of Executive Function–Adult Version (BRIEF-A). Lutz, FL: Psychological Assessment Resources. source

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Hochberg's p-value adjustment method was used to control for potential multiplicity issues when analyzing the four component scores of the Behavioral Regulation Index and the five component scores of the Metacognitive Index.

    “Hochberg’s p-value adjustment method was used to control for potential multiplicity issues when analyzing the four component scores of the Behavioral Regulation Index and the five component scores of the Metacognitive Index.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    A post-hoc mixed model repeated measures (MMRM) analysis on the GEC score was performed as a sensitivity analysis.

    “Additionally, a post-hoc mixed model repeated measures (MMRM) analysis on the GEC score with terms for baseline score, treatment, investigator, visit, treatment-by-visit interaction (time-by-treatment), and baseline-score-by-visit interaction was performed as a sensitivity analysis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Of 584 participants screened, 445 were randomized (220 atomoxetine; 225 placebo), and 385 received at least 1 dose of study drug.

    “Of the 584 participants screened, 445 were randomized to treatment (220 atomoxetine; 225 placebo), and 385 received at least 1 dose of study drug.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Atomoxetine was approved for use in adults (age 18 and older) with ADHD based on 2 pivotal, randomized, placebo-controlled trials.

    “Atomoxetine was approved for use in adults (age 18 and older) with ADHD based on 2 pivotal, randomized, placebo-controlled trials [15].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] D Michelson, 2003, Atomoxetine in adults with ADHD: two randomized, placebo-controlled studies, Biol Psychiatry source

  • May combine two claims.

    Interpretationown data

    The atomoxetine treatment effect on BRIEF-A Global Executive Composite was clinically relevant and small to moderate.

    “indicating a clinically relevant small to moderate effect [21]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] CJ Ferguson, 2009, An effect size primer: a guide for clinicians and researchers, Professional Psychol Res Pract source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The ACDS v1.2 is a validated, structured diagnostic scale for adult ADHD.

    “The ACDS v1.2 is a validated, structured diagnostic scale for adult ADHD, containing separate modules of assessment of childhood and adulthood ADHD symptoms and impairments, which establishes whether a DSM-IV-TR diagnosis of adult ADHD is present or not [17].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] LA Adler, 2004, Diagnosis and evaluation of adults with attention-deficit/hyperactivity disorder, Psychiatr Clin N Am source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Atomoxetine hydrochloride is a nonstimulant, selective norepinephrine reuptake inhibitor approved in the US as a treatment for ADHD in children, adolescents, and adults.

    “Atomoxetine hydrochloride is a nonstimulant, selective norepinephrine reuptake inhibitor approved in the US as a treatment for ADHD in children, adolescents, and adults, as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Text Revision (DSM-IV-TR) [14].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] American Psychiatric Association (2000) Diagnostic and statistical manual of mental disorders. 4th ed. Text revised. Washington, DC: American Psychiatric Association.

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Assignment to treatment groups was determined by a computer-generated random sequence using an interactive voice response system at the site level in a double-blind fashion.

    “Participants were randomized 1∶1 to either the atomoxetine or placebo group at the site level in a double-blinded manner, determined by a computer-generated random sequence using an interactive voice response system.”
    • Also stated in: § Statistical Analyses · plain
      “Assignment to treatment groups was determined by a computer-generated random sequence using an interactive voice response system at the site level in a double-blind fashion.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    For the BRIEF-A analyses, only patients with baseline and at least one postbaseline BRIEF-A measurement were included: atomoxetine N=161 and placebo N=167.

    “For this paper, which is focused on BRIEF-A results, only patients with baseline and at least one postbaseline BRIEF-A measurement were included in analyses: atomoxetine (N = 161) and placebo (N = 167).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In a phase 4 study, atomoxetine was observed to reduce ADHD symptoms and improve quality of life in young adults compared with placebo.

    “In a phase 4 study that focused on prospectively assessing the efficacy and safety of atomoxetine in young adults, atomoxetine was observed to reduce ADHD symptoms and improve quality of life in young adults compared with placebo [16].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] TM Durell, 2013, Atomoxetine treatment of attention-deficit/hyperactivity disorder in young adults with assessment of functional outcomes: a randomized, double-blind, placebo-controlled clinical trial, J Clin Psychopharmacol source

  • May combine two claims.

    Interpretationown data

    Results from the three validity scales built into the BRIEF-A suggest valid self-reporting when completing the BRIEF-A assessment and provide strength to the merit of the atomoxetine versus placebo results.

    “results from the three validity scales built into the BRIEF-A suggest valid self-reporting when completing the BRIEF-A assessment and provide strength to the merit of the atomoxetine versus placebo results.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The BRIEF-A validity scales are adequate to establish valid self-reporting.

  • May combine two claims.

    Study design and conductnone given

    This study had a higher-than-expected drop out rate, which could have reduced the power of the study.

    “Additionally, this study had a higher-than-expected drop out rate, which could have reduced the power of the study.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductreasoning

    The study was conducted with written informed consent and approval by each participating site's institutional review board, in accordance with the Declaration of Helsinki and Good Clinical Practices.

    “Before initiation of any study procedures, site investigators provided participants with thorough verbal and written descriptions of protocol requirements, and participants gave written consent under procedures approved by each participating site’s institutional review board, which included: New England Institutional Review Board (IRB), University of Kentucky IRB, Western IRB, New York University”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    Sample size was selected to allow for more than 80% power on the primary efficacy measure (CAARS) rather than secondary measures.

    “Sample size was selected to allow for more than 80% power on the primary efficacy measure (CAARS) rather than secondary measures.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Some aspects of executive functioning in patients with neurocognitive deficits caused by diseases other than ADHD have been shown to improve with administration of stimulants.

    “some aspects of executive functioning in patients with neurocognitive deficits caused by diseases other than ADHD have been shown to improve with administration of stimulants [32], [33].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [32] SA Morrow, 2013, Lisdexamfetamine dimesylate improves processing speed and memory in cognitively impaired MS patients: a phase II study, J Neurol source
    • cites [33] K Gehring, 2012, A randomized trial on the efficacy of methylphenidate and modafinil for improving cognitive functioning and symptoms in patients with a primary brain tumor, J Neurooncol source

  • Classified as probably not a substantial claim.

    Premisecitation

    Higher BRIEF-A scores indicate greater executive functioning impairment.

    “Higher BRIEF-A scores indicate greater executive functioning impairment.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] Roth RM, Isquith PK, Gioia GA (2005) Behavior Rating Inventory of Executive Function–Adult Version (BRIEF-A). Lutz, FL: Psychological Assessment Resources. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    There was an absence of formal informant ADHD ratings in this study.

    “Although not commonly used in adult ADHD trials [34], there was an absence of formal informant ADHD ratings.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] LA Adler, 2008, The reliability and validity of self- and investigator ratings of ADHD in adults, J Attention Disorders source

  • Classified as probably not a substantial claim.

    Premisecitation

    The BRIEF-A has advantages as a behavioral rather than neuropsychological assessment of executive functioning in that it relies on ratings of real-world life activities.

    “The BRIEF-A has advantages as a behavioral rather than neuropsychological assessment of executive functioning in that it relies on ratings of real-world life activities [26].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] RA Barkley, 2011, Predicting impairment in major life activities and occupational functioning in hyperactive children as adults: self-reported executive function (EF) deficits versus EF tests, Dev Neuropsychol source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The BRIEF-A assessments were only conducted at baseline, Week 5, and Week 12.

    “The BRIEF-A assessments were only conducted at baseline, Week 5, and Week 12.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    For the BRIEF-A analyses, only those patients with both a baseline and post-baseline measurement were included.

    “For the BRIEF-A analyses, only those patients with both a baseline and post-baseline measurement were included.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In the atomoxetine study using the BADDS to assess executive functioning, the emotion domain had the lowest baseline BADDS cluster score and the lowest mean change from baseline score, but the effect of atomoxetine on reducing the emotion cluster score was statistically significantly greater than placebo.

    “in the atomoxetine study using the BADDS to assess executive functioning, the emotion domain had the lowest baseline BADDS cluster score and the lowest mean change from baseline score; but, in this case, the effect of atomoxetine on reducing the emotion cluster score was statistically significantly greater than placebo [4].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] TE Brown, 2011, Effect of atomoxetine on executive function impairments in adults with ADHD, J Atten Disord source

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Interpretation of the currently presented BRIEF-A results should be tempered by the absence of neuropsychological assessments of executive function.

    “Interpretation of the currently presented BRIEF-A results should be tempered by the absence of neuropsychological assessments of executive function.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Atomoxetine may affect executive functioning via its actions on norepinephrine levels in the central nervous system.

    “Thus, atomoxetine may affect executive functioning via its actions on norepinephrine levels in the central nervous system.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    Atomoxetine's effect on dopamine levels could also play a role in signaling that affects executive function.

    “This could also play a role in signaling that affects executive function.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Neuropsychological testing was largely found to identify patients with lower IQ and achievement testing, while behavioral questionnaire assessment chiefly identified patients with higher levels of ADHD symptoms, psychiatric comorbidity, and interpersonal deficits.

    “Neuropsychological testing was largely found to identify patients with lower IQ and achievement testing, while behavioral questionnaire assessment chiefly identified patients with higher levels of ADHD symptoms, psychiatric comorbidity, and interpersonal deficits.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] J Biederman, 2008, Discordance between psychometric testing and questionnaire-based definitions of executive function deficits in individuals with ADHD, J Attention Disorders source
39 of 39

  • The paper relies on this without support.

    The sample of young adults with ADHD in this trial is representative of young adults with ADHD generally.

    “Statistically significantly greater improvement in executive function was observed in young adults with ADHD in the atomoxetine versus placebo group as measured by changes in the BRIEF-A scales.”

  • The paper relies on this without support.

    Changes in BRIEF-A scores reflect changes in executive function.

    “Statistically significantly greater improvement in executive function was observed in young adults with ADHD in the atomoxetine versus placebo group as measured by changes in the BRIEF-A scales.”

  • The paper relies on this without support.

    Non-significant differences on the BRIEF-A validity scales indicate valid responding.

    “In addition, the validity scales: Inconsistency (p = .644), Infrequency (p = .097), and Negativity (p = .456) were not statistically significant, showing scale validity.”

  • The paper relies on this without support.

    The BRIEF-A subscales cover 75 items within 9 nonoverlapping clinical scales measuring various aspects of executive functioning.

    “the BRIEF-A subscales cover 75 items within 9 nonoverlapping clinical scales measuring various aspects of executive functioning (inhibition, shifting, emotion, self-monitoring, initiation, memory, planning/organizing, monitoring, and organization)”

  • The paper relies on this without support.

    A BRIEF-A Global Executive Composite T-score ≥60 indicates impairment greater than 2 standard deviations from the mean.

    “which shows an impairment of greater than 2 standard deviations from the mean”

  • The paper relies on this without support.

    The BRIEF-A validity scales are adequate to establish valid self-reporting.

    “results from the three validity scales built into the BRIEF-A suggest valid self-reporting when completing the BRIEF-A assessment”
6 of 6

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Discussion overstates the number of significantly improved subscales

    Major

    The discussion says atomoxetine significantly improved seven of nine BRIEF-A subscales, but the results identify four subscales without a statistically significant between-group difference. That leaves five, not seven, with significant differences.

1 of 1

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Authors
Adler, L. A., Clemow, D. B., Williams, D. W., & Durell, T. M.
Affiliations
  • New York University (US)
  • Eli Lilly (United States) (US)
Corresponding author
Clemow, David B.
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2014-08-22
Volume
9
Issue
8
Pages
e104175
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0104175
PMC
PMC4141744
OpenAlex
W2009260504
Semantic Scholar
a0faeb1d263b04b611b7947d94859fe311ddf25a
Cited by
32
References
34
Citations by year
2026: 3 · 2025: 1 · 2024: 3 · 2023: 2 · 2022: 1 · 2021: 4 · 2019: 3 · 2018: 3 · 2017: 5 · 2016: 3 · 2015: 4
FWCI
3.07
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • Bristol-Myers Squibb
  • Eli Lilly and Company
  • Pfizer
  • Major League Baseball
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
  • Social Sciences › Psychology › Neuropsychology and Physiological Psychology › Developmental and Educational Neuropsychology
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
Keywords
atomoxetine, attention deficit hyperactivity disorder, executive function, young adults, BRIEF-A, stimulant medication, behavioral regulation, metacognition, working memory, inhibitory control, self-monitoring, task organization
MeSH terms
Atomoxetine Hydrochloride, Adult, Attention Deficit Disorder with Hyperactivity, Female, Humans, Male, Propylamines, Treatment Outcome, Adrenergic Uptake Inhibitors, Young Adult, Executive Function

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

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