Contact Us

For Marketing, Sales and Subscriptions Inquiries
2637 E Atlantic Blvd #43110
Pompano Beach, FL 33062

Conference List

Journal of Brain Sciences

July 2015, Volume 1, 2, pp 43-53

Evidence of A Pharmacological Dissociation Between The Robust Effects of Methylphenidate on Adhd Symptoms and Weaker Effects on Working Memory

Joseph Biederman


James Chan


Thomas J. Spencer


K. Yvonne Woodworth


Tara Kenworthy


Ronna Fried


Pradeep Bhide


Stephen V. Faraone

Joseph Biederman 1 

James Chan 2 Thomas J. Spencer 1 K. Yvonne Woodworth 2 ,
Tara Kenworthy 2 Ronna Fried 1 Pradeep Bhide 7
Stephen V. Faraone 8

  1. Clinical and Research Programs in Pediatric Psychopharmacology and Adult ADHD, Massachusetts General Hospital, Fruit Street, Warren, Boston, MA, USA; Harvard Medical School, Fruit Street, Warren, Boston, MA, USA 1

  2. Clinical and Research Programs in Pediatric Psychopharmacology and Adult ADHD, Massachusetts General Hospital, Fruit Street, Warren, Boston, MA, USA 2

  3. Florida State University College of Medicine, West Call Street, Tallahassee, FL, USA 7

  4. SUNY Upstate Medical University, Weiskotten Hall, Syracuse, NY, USA 8

Pages: 43-53

DOI: 10.18488/journal.83/2015.1.2/

Share :


Working memory (WM) deficits often co-occur with, but do not define, attention deficit hyperactivity disorder (ADHD). Preclinical and neuroimaging studies show that ADHD and WM deficits are dissociated at the level of individual dopamine receptor function. We hypothesized that there would also be a pharmacological dissociation of the effects of stimulants on ADHD and WM. ADHD subjects were derived from three prospective clinical trials involving treatment with OROS methylphenidate for at least 6 weeks. Subjects were adolescents and adults with DSM-IV ADHD with systematic assessments of WM and ADHD symptoms. Cohen’s d was used to evaluate effect size between baseline and week 6 for all assessments, and Pearson correlations were used to evaluate the relationship between assessments at baseline and between change scores for assessments from baseline to week 6. Cohen’s d estimates for the Cambridge Neuropsychological Test Automated Battery spatial working memory measures differed significantly by 1.8 standard deviations (t= -10.8, df= 70, p < 0.001) and 1.9 standard deviations (t= -11.1, df= 70, p < 0.001) for the strategy and total between errors subcategories respectively. Confidence intervals did not overlap with those of the Adult ADHD Investigator Symptom Rating Scale (AISRS). A similar effect was observed for changes in AISRS and the Behavior Rating Inventory of Executive Function working memory scale where the Cohen’s d estimates differed significantly by 1.1 standard deviations (t= -2.5, df= 137, p = 0.015) and confidence intervals did not overlap. These findings provide further evidence for the dissociation between ADHD and WM deficits.
Contribution/ Originality
This study documents that responses to methylphenidate in ADHD symptoms and working are dissociated, indicating that a sizeable number of ADHD subjects may continue to struggle with residual working memory impairments despite good clinical response to methylphenidate.




  1. S. N. Visser, "Trends in the parent-report of health care provider-diagnosed and medicated attention-deficit/hyperactivity disorder: United States, 2003-2011," J. Am. Acad. Child Adolesc. Psychiatry, vol. 53, pp. 34-46 e2, 2014.
  2. R. C. Kessler, "The prevalence and correlates of adult ADHD in the United States: Results from the national comorbidity survey replication," Am. J. Psychiatry, vol. 163, pp. 716-723, 2006.
  3. J. Biederman, "Attention deficit hyperactivity disorder: A selective overview," Biol. Psychiatry, vol. 57, pp. 1215-1220, 2005.
  4. G. Bush, E. M. Valera, and L. J. Seidman, "Functional neuroimaging of attention-deficit/hyperactivity disorder: A review and suggested future directions," Biol. Psychiatry, vol. 57, pp. 1273-1284, 2005.
  5. S. Cortese, "Toward systems neuroscience of ADHD: A meta-analysis of 55 fMRI studies," Am. J. Psychiatry, vol. 169, pp. 1038-1055, 2012.
  6. H. Hart, "Meta-analysis of functional magnetic resonance imaging studies of inhibition and attention in attention-deficit/hyperactivity disorder: Exploring task-specific, stimulant medication, and age effects," JAMA Psychiatry, vol. 70, pp. 185-198, 2013.
  7. J. Biederman, "Stability of executive function deficits into young adult years: A prospective longitudinal follow-up study of grown up males with ADHD," Acta Psychiatr. Scand., vol. 116, pp. 129-136, 2007.
  8. J. Biederman, "Impact of psychometrically defined deficits of executive functioning in adults with attention deficit hyperactivity disorder," Am. J. Psychiatry, vol. 163, pp. 1730-1738, 2006.
  9. R. A. Barkley and K. R. Murphy, "Impairment in occupational functioning and adult ADHD: The predictive utility of executive function (EF) ratings versus EF tests," Arch. Clin. Neuropsychol, vol. 25, pp. 157-73, 2010.
  10. S. V. Faraone, "Neuropsychological studies of late onset and subthreshold diagnoses of adult attention-deficit/hyperactivity disorder," Biol. Psychiatry, vol. 60, pp. 1081-1087, 2006.
  11. R. M. Alderson, "Attention-deficit/hyperactivity disorder (ADHD) and working memory in adults: A meta-analytic review," Neuropsychology, vol. 27, pp. 287-302, 2013.
  12. J. Biederman, "Impact of executive function deficits and ADHD on academic outcomes in children," J. Consult. Clin. Psychol., vol. 72, pp. 757-766, 2004.
  13. K. Lee, "Working memory deficits produced by prenatal nicotine exposure are associated with deficits in DRD4 receptor activity," presented at the The Society for Neuroscience Annual Meeting, San Diego, 2013.
  14. K. Lee, "Hyperactivity and working memory deficits induced by prenatal nicotine exposure are associated with dopamine D1 and D4 receptor dysfunction," presented at the The Society for Neuroscience Annual Meeting, Washington, D.C, 2014.
  15. S. V. Faraone and S. J. Glatt, "A comparison of the efficacy of medications for adult attention-deficit/hyperactivity disorder using meta-analysis of effect sizes," J. Clin. Psychiatry, vol. 71, pp. 754-763, 2009.
  16. Canadian ADHD Resource Alliance, "Canadian ADHD practice guidelines." Available: [Accessed June 1, 2010], 2008.
  17. J. J. Kooij, "Efficacy and safety of methylphenidate in 45 adults with attention-deficit/hyperactivity disorder. A randomized placebo-controlled double-blind cross-over trial," Psychol. Med., vol. 34, pp. 973-982, 2004.
  18. S. V. Faraone and J. Buitelaar, "Comparing the efficacy of stimulants for ADHD in children and adolescents using meta-analysis," Eur. Child Adolesc. Psychiatry, vol. 19, pp. 353-364, 2009.
  19. S. V. Faraone, "Understanding the effect size of lisdexamfetamine dimesylate for treating ADHD in children and adults," J. Atten. Disord., vol. 16, pp. 128-137, 2012.
  20. R. H. Pietrzak, "Cognitive effects of immediate-release methylphenidate in children with attention-deficit/hyperactivity disorder," Neurosci. Biobehav. Rev., vol. 30, pp. 1225-1245, 2006.
  21. P. Fray, T. W. Robbins, and B. J. Sahakian, "Neuropsychiatric applications of CANTAB," Int. J. Geriatr. Psychiatry, vol. 11, pp. 329-336, 1996.
  22. R. Roth, P. Isquith, and G. Gioia, Brief-A behavior rating inventory of executive function-adult version, publication manual. Lutz: Psychological Assessment Resources, Inc, 2005.
  23. G. A. Gioia, BRIEF behavior rating Inventory of executive function: Manual. Lutz, Fl: Psychological Assessment Resources, 2000.
  24. American Psychiatric Association, Diagnostic and statistical manual of mental disorders: Fourth edition text revision (DSM-IV-TR). Washington, DC: American Psychiatric Association, 2000.
  25. J. Biederman, "A randomized, placebo-controlled trial of OROS-methylphenidate in adults with attention-deficit/hyperactivity disorder," Biol. Psychiatry, vol. 59, pp. 829-835, 2006.
  26. P. Hammerness, "Do stimulants reduce the risk for cigarette smoking in youth with attention-deficit hyperactivity disorder? A prospective, long-term, open-label study of extended-release methylphenidate," J. Pediatr., vol. 162, pp. 22-7 e2, 2013.
  27. J. Biederman, "Memantine in the treatment of executive function deficits in adults with ADHD: A pilot-randomized double-blind controlled clinical trial," J. Atten. Disord., 2014.
  28. T. J. Spencer, "Validation of the adult ADHD investigator symptom rating scale (AISRS)," J. Atten. Disord., vol. 14, pp. 57-68, 2010.
  29. M. Luciana, "Practitioner review: Computerized assessment of neuropsychological function in children: Clinical and research applications of the Cambridge neuropsychological testing automated battery (CANTAB)," J. Child Psychol. Psychiatry, vol. 44, pp. 649-663, 2003.
  30. M. Luciana and C. A. Nelson, "The functional emergence of prefrontally-guided working memory systems in four- to eight-year-old children," Neuropsychologia, vol. 36, pp. 273-293, 1998.
  31. M. Luciana and C. A. Nelson, "Assessment of neuropsychological function through use of the Cambridge neuropsychological testing automated battery: Performance in 4- to 12-year-old children," Dev. Neuropsychol, vol. 22, pp. 595-624, 2002.
  32. T. E. Brown and J. M. Landgraf, "Improvements in executive function correlate with enhanced performance and functioning and health-related quality of life: Evidence from 2 large, double-blind, randomized, placebo-controlled trials in ADHD," Postgrad. Med., vol. 122, pp. 42-51, 2010.
  33. J. Biederman, "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, vol. 21, pp. 508-515, 2011.
  34. J. Biederman, "Discordance between psychometric testing and questionnaire-based definitions of executive function deficits in individuals with ADHD," J. Atten. Disord., vol. 12, pp. 92-102, 2008.
  35. J. Swanson, R. D. Baler, and N. D. Volkow, "Understanding the effects of stimulant medications on cognition in individuals with attention-deficit hyperactivity disorder: A decade of progress," Neuropsychopharmacology, vol. 36, pp. 207-226, 2011.
  36. S. M. Berman, "Potential adverse effects of amphetamine treatment on brain and behavior: A review," Mol. Psychiatry, vol. 14, pp. 123-42, 2009.
  37. I. F. Arnsten, "Toward a new understanding of attention-deficit hyperactivity disorder pathophysiology: An important role for prefrontal cortex dysfunction," CNS Drugs, vol. 23, pp. 33-41, 2009.
  38. K. E. Browman, "A-412997, aselective dopamine D4 agonist, improves cognitive performance in rats," Pharmacology, Biochemistry, and Behavior, vol. 82, pp. 148-155, 2005.
  39. R. A. Barkley, "Behavioral inhibition, sustained attention, and executive functions: Constructing a unifying theory of ADHD," Psychol. Bull., vol. 121, pp. 65-94, 1997.
  40. M. C. Etchepareborda and L. Abad-Mas, "Working memory in basic learning processes," Rev. Neurol., vol. 40, pp. S79-83, 2005.
  41. J. D. Cohen, "Activation of the prefrontal cortex in a nonspatial working memory task with functional MRI," Human Brain Mapping, vol. 1, pp. 293-304, 1994.
  42. J. Biederman, "Effects of stimulant medication on neuropsychological functioning in young adults with attention-deficit/hyperactivity disorder," J. Clin. Psychiatry, vol. 69, pp. 1150-1156, 2008.
  43. I. M. Snyder, "Effect of treatment with stimulant medication on nonverbal executive function and visuomotor speed in children with attention deficit/hyperactivity disorder (ADHD)," Child Neuropsychol, vol. 14, pp. 211-226, 2008.


Google Scholor ideas Microsoft Academic Search bing Google Scholor


Competing Interests:


Related Article