Clinical Practice & Epidemiology in Mental Health




ISSN: 1745-0179 ― Volume 16, 2020
RESEARCH ARTICLE

Clinical and Neuropsychological Predictors of Methylphenidate Response in Children and Adolescents with ADHD: A Naturalistic Follow-up Study in a Spanish Sample



María Vallejo-Valdivielso1, 3, *, Pilar de Castro-Manglano2, 3, Azucena Díez-Suárez1, 3, Juan J. Marín-Méndez4, Cesar A. Soutullo1, 2, 3
1 Child & Adolescent Psychiatry Unit, Department of Psychiatry & Medical Psychology, University of Navarra Clinic, Pamplona, Navarra, Spain
2 Child & Adolescent Psychiatry Unit, Department of Psychiatry & Medical Psychology, University of Navarra Clinic, Madrid, Spain
3 IDISNA (Health Research Institute of Navarra - Instituto de Investigación Sanitaria de Navarra), Navarra, Spain
4 Pharmamodelling Inc, Navarra, Spain

Abstract

Background:

Methylphenidate (MPH) is the most commonly used medication for Attention-Deficit/Hyperactivity Disorder (ADHD), but to date, there are neither consistent nor sufficient findings on conditions differentiating responsiveness to MPH response in ADHD.

Objective:

To develop a predictive model of MPH response, using a longitudinal and naturalistic follow-up study, in a Spanish sample of children and adolescents with ADHD.

Methods:

We included all children and adolescents with ADHD treated with MPH in our outpatient Clinic (2005 to 2015), evaluated with the K-SADS interview. We collected ADHD-RS-IV.es and CGI-S scores at baseline and at follow up, and neuropsychological testing (WISC-IV, Continuous Performance Test (CPT-II) & Stroop). Clinical response was defined as >30% reduction from baseline of total ADHD-RS-IV.es score and CGI-S final score of 1 or 2 maintained for the previous 3 months.

Results:

We included 518 children and adolescents with ADHD, mean (SD) age of patients was 11.4 (3.3) years old; 79% male; 51.7% had no comorbidities; and 75.31% had clinical response to a mean MPH dose of 1.2 mg/kg/day. Lower ADHD-RS-IV.es scores, absence of comorbidities (oppositional-defiant symptoms, depressive symptoms and alcohol/cannabis use), fewer altered neuropsychological tests, higher total IQ and low commission errors in CPT-II, were significantly associated with a complete clinical response to methylphenidate treatment.

Conclusion:

Oppositional-defiant symptoms, depressive symptoms, and a higher number of impaired neuropsychological tests are associated with worse clinical response to methylphenidate. Other stimulants or non-stimulants treatment may be considered when these clinical and neuropsychological variables converged in the first clinical interview.

Keywords: ADHD, Predictive factors, Neuropsychological variables, Methylphenidate, Treatment, Spanish sample.


Article Information


Identifiers and Pagination:

Year: 2019
Volume: 15
First Page: 160
Last Page: 171
Publisher Id: CPEMH-15-160
DOI: 10.2174/1745017901915010160

Article History:

Received Date: 28/06/2019
Revision Received Date: 12/11/2019
Acceptance Date: 15/11/2019
Electronic publication date: 31/12/2019
Collection year: 2019

© 2019 Vallejo-Valdivielso et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: (https://creativecommons.org/licenses/by/4.0/legalcode). This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at the Child & Adolescent Psychiatry Unit, Department of Psychiatry & Medical Psychology, University of Navarra Clinic, Ave. Pío XII 36, 31008, Pamplona, Navarra, Spain; Tel: 0034645686345; Fax: 0034948296500; E-mail: mvvaldiviel@unav.es





1. INTRODUCTION

Attention-Deficit/Hyperactivity Disorder (ADHD) is a heterogeneous neurodevelopmental disorder defined as developmentally inappropriate levels of hyperactivity, impulsivity and/or inattention [1American Psychiatric Association (APA). Diagnostic and statistical manual of mental disorders 2013., 2Faraone SV, Asherson P, Banaschewski T, et al. Attention-deficit/hyperactivity disorder. Nat Rev Dis Primers 2015; 1: 15020-0.
[http://dx.doi.org/10.1038/nrdp.2015.20] [PMID: 27189265]
]. Prevalence is stable internationally, with rates in children and adolescents of 7.2% (95% CI 6.7-7.8) [3Polanczyk GV, Salum GA, Sugaya LS, Caye A, Rohde LA. Annual research review: A meta-analysis of the worldwide prevalence of mental disorders in children and adolescents. J Child Psychol Psychiatry 2015; 56(3): 345-65.
[http://dx.doi.org/10.1111/jcpp.12381] [PMID: 25649325]
, 4Thomas R, Sanders S, Doust J, Beller E, Glasziou P. Prevalence of attention-deficit/hyperactivity disorder: a systematic review and meta-analysis. Pediatrics 2015; 135(4): e994-e1001.
[http://dx.doi.org/10.1542/peds.2014-3482] [PMID: 25733754]
]. Boys: girls’ ratio is 3-4:1 in epidemiological samples [3Polanczyk GV, Salum GA, Sugaya LS, Caye A, Rohde LA. Annual research review: A meta-analysis of the worldwide prevalence of mental disorders in children and adolescents. J Child Psychol Psychiatry 2015; 56(3): 345-65.
[http://dx.doi.org/10.1111/jcpp.12381] [PMID: 25649325]
] and 7-8:1 in clinical samples, suggesting referral bias against girls [5Thapar A, Cooper M. Attention deficit hyperactivity disorder. Lancet 2016; 387(10024): 1240-50.
[http://dx.doi.org/10.1016/S0140-6736(15)00238-X] [PMID: 26386541]
]. A gold standard assessment for diagnoses should include structured clinical interviews with the patient and parents, information from teachers’ questionnaires or interviews [6Biederman J, Faraone SV, Monuteaux MC, Grossbard JR. How informative are parent reports of attention-deficit/hyperactivity disorder symptoms for assessing outcome in clinical trials of long-acting treatments? A pooled analysis of parents’ and teachers’ reports. Pediatrics 2004; 113(6): 1667-71.
[http://dx.doi.org/10.1542/peds.113.6.1667] [PMID: 15173489]
] and neuropsychological evaluation of intellectual function and Executive Function (EF) [7Bledsoe JC, Xiao D, Chaovalitwongse A, et al. Diagnostic Classification of ADHD Versus Control: Support Vector Machine Classification Using Brief Neuropsychological Assessment. J Atten Disord 2016.1087054716649666
[http://dx.doi.org/10.1177/1087054716649666] [PMID: 27231214]
].

ADHD may be associated with multiple neuropsychological deficits [8Coghill DR, Seth S, Matthews K. A comprehensive assessment of memory, delay aversion, timing, inhibition, decision making and variability in attention deficit hyperactivity disorder: advancing beyond the three-pathway models. Psychol Med 2014; 44(9): 1989-2001.
[http://dx.doi.org/10.1017/S0033291713002547] [PMID: 24176104]
-12Douglas VI. Stop, look and listen: The problem of sustained attention and impulse control in hyperactive and normal children. Can J Behav Sci 1972; 4: 259-82.
[http://dx.doi.org/10.1037/h0082313]
], particularly in the measures of EF [13Schoemaker K, Mulder H, Deković M, Matthys W. Executive functions in preschool children with externalizing behavior problems: a meta-analysis. J Abnorm Child Psychol 2013; 41(3): 457-71.
[http://dx.doi.org/10.1007/s10802-012-9684-x] [PMID: 23054130]
-17Miyake A, Friedman NP, Emerson MJ, Witzki AH, Howerter A, Wager TD. The unity and diversity of executive functions and their contributions to complex “Frontal Lobe” tasks: a latent variable analysis. Cognit Psychol 2000; 41(1): 49-100.
[http://dx.doi.org/10.1006/cogp.1999.0734] [PMID: 10945922]
]. These studies conclude that the differences between ADHD and controls are focused on inhibition [18Barkley RA. Behavioral inhibition, sustained attention, and executive functions: constructing a unifying theory of ADHD. Psychol Bull 1997; 121(1): 65-94.
[http://dx.doi.org/10.1037/0033-2909.121.1.65] [PMID: 9000892]
], working memory [19Coghill DR, Rhodes SM, Matthews K. The neuropsychological effects of chronic methylphenidate on drug-naive boys with attention-deficit/hyperactivity disorder. Biol Psychiatry 2007; 62(9): 954-62.
[http://dx.doi.org/10.1016/j.biopsych.2006.12.030] [PMID: 17543895]
, 20Rhodes SM, Coghill DR, Matthews K. Methylphenidate restores visual memory, but not working memory function in attention deficit-hyperkinetic disorder. Psychopharmacology (Berl) 2004; 175(3): 319-30.
[http://dx.doi.org/10.1007/s00213-004-1833-7] [PMID: 15138760]
], attentional set-shifting and planning [21Rhodes SM, Coghill DR, Matthews K. Neuropsychological functioning in stimulant-naive boys with hyperkinetic disorder. Psychol Med 2005; 35(8): 1109-20.
[http://dx.doi.org/10.1017/S0033291705004599] [PMID: 16116937]
, 22Kempton S, Vance A, Maruff P, Luk E, Costin J, Pantelis C. Executive function and attention deficit hyperactivity disorder: stimulant medication and better executive function performance in children. Psychol Med 1999; 29(3): 527-38.
[http://dx.doi.org/10.1017/S0033291799008338] [PMID: 10405075]
], reaction time variability [23Tamm L, Narad ME, Antonini TN, O’Brien KM, Hawk LW Jr, Epstein JN. Reaction time variability in ADHD: A review. Neurotherapeutics 2012; 9(3): 500-8.
[http://dx.doi.org/10.1007/s13311-012-0138-5] [PMID: 22930417]
, 24Castellanos FX, Sonuga-Barke EJS, Milham MP, Tannock R. Characterizing cognition in ADHD: beyond executive dysfunction. Trends Cogn Sci (Regul Ed) 2006; 10(3): 117-23.
[http://dx.doi.org/10.1016/j.tics.2006.01.011] [PMID: 16460990]
], and emotional dysregulation [25Shaw P, Stringaris A, Nigg J, Leibenluft E. Emotion dysregulation in attention deficit hyperactivity disorder. Am J Psychiatry 2014; 171(3): 276-93.
[http://dx.doi.org/10.1176/appi.ajp.2013.13070966] [PMID: 24480998]
]. However, not all children with ADHD have EF deficits [8Coghill DR, Seth S, Matthews K. A comprehensive assessment of memory, delay aversion, timing, inhibition, decision making and variability in attention deficit hyperactivity disorder: advancing beyond the three-pathway models. Psychol Med 2014; 44(9): 1989-2001.
[http://dx.doi.org/10.1017/S0033291713002547] [PMID: 24176104]
, 26Sjöwall D, Bohlin G, Rydell AM, Thorell LB. Neuropsychological deficits in preschool as predictors of ADHD symptoms and academic achievement in late adolescence. Child Neuropsychol 2015; 1-18.
[http://dx.doi.org/10.1080/09297049.2015.1063595] [PMID: 26212755]
], some patients display a single deficit, while others suffer multiple deficits [27Nigg JT, Willcutt EG, Doyle AE, Sonuga-Barke EJS. Causal heterogeneity in attention-deficit/hyperactivity disorder: do we need neuropsychologically impaired subtypes? Biol Psychiatry 2005; 57(11): 1224-30.
[http://dx.doi.org/10.1016/j.biopsych.2004.08.025] [PMID: 15949992]
, 28Doyle AE, Biederman J, Seidman LJ, Weber W, Faraone SV. Diagnostic efficiency of neuropsychological test scores for discriminating boys with and without attention deficit-hyperactivity disorder. J Consult Clin Psychol 2000; 68(3): 477-88.
[http://dx.doi.org/10.1037/0022-006X.68.3.477] [PMID: 10883564]
].

Available psychopharmacological treatments with good to moderate effect sizes include stimulants (methylphenidate and lisdexamfetamine), and non-stimulants medications (atomoxetine and alfa-agonist agents guanfacine and clonidine) [29Coghill DR, Banaschewski T, Soutullo C, Cottingham MG, Zuddas A. Systematic review of quality of life and functional outcomes in randomized placebo-controlled studies of medications for attention-deficit/hyperactivity disorder. Eur Child Adolesc Psychiatry 2017; 26(11): 1283-307.
[http://dx.doi.org/10.1007/s00787-017-0986-y] [PMID: 28429134]
]. About 66% of studies, showed positive cognitive effects with MPH treatment [30Pietrzak RH, Mollica CM, Maruff P, Snyder PJ. Cognitive effects of immediate-release methylphenidate in children with attention-deficit/hyperactivity disorder. Neurosci Biobehav Rev 2006; 30(8): 1225-45.
[http://dx.doi.org/10.1016/j.neubiorev.2006.10.002] [PMID: 17161238]
]. However, not all patients have an optimal clinical response to treatment [31van der Schaaf ME, Fallon SJ, Ter Huurne N, Buitelaar J, Cools R. Working memory capacity predicts effects of methylphenidate on reversal learning. Neuropsychopharmacology 2013; 38(10): 2011-8.
[http://dx.doi.org/10.1038/npp.2013.100] [PMID: 23612436]
]. Whilst around 65% of children diagnosed with ADHD tolerate and respond to Methylphenidate (MPH), 35% will not [32Johnston BA, Coghill D, Matthews K, Steele JD. Predicting methylphenidate response in attention deficit hyperactivity disorder: a preliminary study. J Psychopharmacol (Oxford) 2015; 29(1): 24-30.
[http://dx.doi.org/10.1177/0269881114548438] [PMID: 25237119]
, 33Hodgkins P, Shaw M, Coghill D, Hechtman L. Amfetamine and methylphenidate medications for attention-deficit/hyperactivity disorder: complementary treatment options. Eur Child Adolesc Psychiatry 2012; 21(9): 477-92.
[http://dx.doi.org/10.1007/s00787-012-0286-5] [PMID: 22763750]
].

One source of suboptimal response could be comorbidity. Given that ADHD is highly comorbid [34Anastopoulos AD, DuPaul GJ, Weyandt LL, et al. 2016.Rates and Patterns of Comorbidity Among First-Year College Students With ADHD ], investigations have studied the potential role of comorbidity in the individual variation of MPH response, but findings were inconclusive. Typically, the best pharmacotherapy response has been obtained in patients with ADHD without comorbidities [35Carpentier PJ, Levin FR. Pharmacological Treatment of ADHD in Addicted Patients: What Does the Literature Tell Us? Harvard review of psychiatry 2017; 25(2): 50-64.]. Few studies have found that ADHD children with or without the presence of anxiety, Conduct Disorder (CD) or Oppositional Defiant Disorders (ODD) responded equally well to MPH [36Chan MH, Leung PW, Ho TP, et al. Neuropsychiatric Disease and Treatment 2017.-39Pliszka SR. Effect of anxiety on cognition, behavior, and stimulant response in ADHD. J Am Acad Child Adolesc Psychiatry 1989; 28(6): 882-7.
[http://dx.doi.org/10.1097/00004583-198911000-00012] [PMID: 2808258]
]. However, other studies found that the presence of comorbid anxiety, ODD, or CD is associated with a worse MPH response [40Ter-Stepanian M, Grizenko N, Zappitelli M, Joober R. Clinical response to methylphenidate in children diagnosed with attention-deficit hyperactivity disorder and comorbid psychiatric disorders. Can J Psychiatry 2010; 55(5): 305-12.
[http://dx.doi.org/10.1177/070674371005500506] [PMID: 20482957]
-42Gray JR, Kagan J. The Challenge of Predicting Which Children with Attention Deficit-Hyperactivity Disorder Will Respond Positively to Methylphenidate. J Appl Dev Psychol 2000; 21(5): 471-89.
[http://dx.doi.org/10.1016/S0193-3973(00)00050-2]
]. Other comorbidities, such as substance use disorder (SUD), present in up to 50% of ADHD patients [43Sullivan MA, Rudnik-Levin F. Attention deficit/hyperactivity disorder and substance abuse. Diagnostic and therapeutic considerations. Ann N Y Acad Sci 2001; 931: 251-70.
[http://dx.doi.org/10.1111/j.1749-6632.2001.tb05783.x] [PMID: 11462745]
], are also associated with worse MPH response in most studies [35Carpentier PJ, Levin FR. Pharmacological Treatment of ADHD in Addicted Patients: What Does the Literature Tell Us? Harvard review of psychiatry 2017; 25(2): 50-64., 44Tamm L, Trello-Rishel K, Riggs P, et al. Predictors of treatment response in adolescents with comorbid substance use disorder and attention-deficit/hyperactivity disorder. J Subst Abuse Treat 2013; 44(2): 224-30.
[http://dx.doi.org/10.1016/j.jsat.2012.07.001] [PMID: 22889694]
].

In the last decades, the interest in finding predictive factors of response to different treatments has increased. Coghill and colleagues, found in a randomized placebo-controlled trial that poor performance on a “delayed matching to sample” (DMtS) task at baseline was the only pre-treatment factor that correlated with clinical response to MPH [19Coghill DR, Rhodes SM, Matthews K. The neuropsychological effects of chronic methylphenidate on drug-naive boys with attention-deficit/hyperactivity disorder. Biol Psychiatry 2007; 62(9): 954-62.
[http://dx.doi.org/10.1016/j.biopsych.2006.12.030] [PMID: 17543895]
]. However, they concluded that their model required a wide range of measures [19Coghill DR, Rhodes SM, Matthews K. The neuropsychological effects of chronic methylphenidate on drug-naive boys with attention-deficit/hyperactivity disorder. Biol Psychiatry 2007; 62(9): 954-62.
[http://dx.doi.org/10.1016/j.biopsych.2006.12.030] [PMID: 17543895]
, 45Denney CB, Rapport MD. Predicting methylphenidate response in children with ADHD: theoretical, empirical, and conceptual models. J Am Acad Child Adolesc Psychiatry 1999; 38(4): 393-401.
[http://dx.doi.org/10.1097/00004583-199904000-00011] [PMID: 10199110]
]. Denney and Rapport also evaluated several MPH response predictive models (empirical, homeostatic, attentional and disinhibition), but none of these models predicted MPH response in children with ADHD. They suggested that a comprehensive model of MPH response would need to include both biological and behavioral components [45Denney CB, Rapport MD. Predicting methylphenidate response in children with ADHD: theoretical, empirical, and conceptual models. J Am Acad Child Adolesc Psychiatry 1999; 38(4): 393-401.
[http://dx.doi.org/10.1097/00004583-199904000-00011] [PMID: 10199110]
].

To date, there are no objective, clinical or biological markers that can robustly predict MPH treatment in patients with ADHD [36Chan MH, Leung PW, Ho TP, et al. Neuropsychiatric Disease and Treatment 2017., 46Kim JW, Sharma V, Ryan ND. Predicting Methylphenidate Response in ADHD Using Machine Learning Approaches. Int J Neuropsychopharmacol 2015; 18(11)pyv052
[http://dx.doi.org/10.1093/ijnp/pyv052] [PMID: 25964505]
]. Given the importance of clinical clues that may help physicians to accurately choose the optimal treatment from each individual patient, our goal is to develop a predictive model of response to MPH based on neuropsychological and clinical variables in a Spanish sample of children and adolescents with ADHD.

2. MATERIALS AND METHODS

2.1. Patients

We included consecutively all drug-naïve patients aged 6 to < 18 years old diagnosed with ADHD treated with methylphenidate for at least three months. We follow them up from January 2000 to April 2015. ADHD was diagnosed according to DSM-IV-TR criteria [47American Psychiatric Association (APA). Diagnostic and statistical manual of mental disorders fourth edition, text revision. 2000.] using a Kiddie-Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version (KSADS-PL) interview template [48Kaufman J, Birmaher B, Brent D, Rao URN. Schedule for Affective Disorders and Schizophrenia for School Aged Children- Present and Lifetime Version (K-SADS-PL) 1996.] by experienced child and adolescent psychiatrists. All clinical data and neuropsychological tests from the routine assessment were collected by unblinded Child & Adolescent Psychiatrists at baseline, defined as the first visit, even if the diagnosis was previously made by other specialists. Patients with commonly comorbid conditions; ODD, CD, mood or anxiety disorder were not excluded from the study. Exclusion criteria included patients with an IQ <80 or with a comorbid neurological disease, or patients with ADHD taking other lisdexamfetamine, atomoxetine or an alfa-agonist agent.

2.2. Materials

2.2.1. Clinical and Neuropsychological Variables

All patients were evaluated twice, at baseline (T1) and in the last follow-up visit, defined as the last recorded visit (T2), with these assessments:

  • Clinical variables
    • The Spanish version of the ADHD-Rating Scale (ADHD-RS-IV.es) [49DuPaul GJ, Power TJ, Anastopoulos AD, Reid R. ADHD Rating Scale-IV: Checklists, norms, and clinical interpretation 1998., 50Vallejo-Valdivielso M, Soutullo CA, de Castro-Manglano P, Marín-Méndez JJ, Díez-Suárez A. Validation of a Spanish-language version of the ADHD Rating Scale IV in a Spanish sample. Neurologia 2017; 2017
      [http://dx.doi.org/10.1016/j.nrl.2017.05.010] [PMID: 28716394]
      ], is an 18-item scale designed to reflect the presence of ADHD-related symptoms of inattention and hyperactivity based on DSM-IV-TR criteria. ADHD-RS-IV.es scores range from 0 to 54, with higher scores indicating more severe symptoms.
    • The SNAP-IV [51Swanson J, Nolan W, Pelham W. The SNAP-IV Rating Scale 1992.], is a 26-item scale which includes the 18 ADHD symptoms (9 for inattentive, 9 for hyperactive/impulsive) and 8 Oppositional and Defiant Disorder symptoms specified in the DSM-IV-TR. In our study, we only used the ODD-subscale score (SNAP-IV ODD-s) to evaluate ODD symptoms.
    • CGI-S (Clinical Global Impressions Severity scale) [52Guy W. ECDEU assessment manual for psychopharmacology, revised Rockvill 1976.], provides an overall clinician-determined summary measure that takes into account all available information and the impact of the symptoms on the patient’s ability to function. It is scored on a scale of 1 (normal, not at all ill) to 7 (severely ill).
  • Neuropsychological variables: IQ, based on:
    • Wechsler Intelligence Scale Revised (WISC-IV) [53Wechsler D. Wechsler Intelligence Scale for Children 2003., 54Wechsler D. Wechsler Intelligence Scale for Children 1991.], T-IQ scores were classified in the following seven levels: ≥130, very superior; 120-129, superior; 110-119, normal-high; 90-109, normal; 80-89, normal-low; 70-79, borderline; and ≤69, intellectual dysfunction/disability.
    • Stroop color word Test (SCWT) [55Stroop J. Studies of interference in serial verbal reaction. J Exp Psychol 1935; 18: 643-62.
      [http://dx.doi.org/10.1037/h0054651]
      ] evaluates the cognitive function of inhibitory control (Interference) in the clinical setting and requires the inhibition of competing responses [56Adleman NE, Menon V, Blasey CM, et al. A developmental fMRI study of the Stroop color-word task. Neuroimage 2002; 16(1): 61-75.
      [http://dx.doi.org/10.1006/nimg.2001.1046] [PMID: 11969318]
      -59Golden C. Stroop Color and Word Test: A Manual for Clinical and experimental uses 1978.].
    • The Conners’ Continuous Performance Test II (CPT-II) [60Conners CK. Conners’ continuous performance test 1995.] that measures the ability to maintain focused attention over longer periods of time (usually 5-20 minutes) while responding to a target stimuli and inhibiting responses to non-target stimuli [61Wang LJ, Huang YS, Chiang YL, Hsiao CC, Shang ZY, Chen CK. Clinical symptoms and performance on the Continuous Performance Test in children with attention deficit hyperactivity disorder between subtypes: a natural follow-up study for 6 months. BMC Psychiatry 2011; 11: 65.
      [http://dx.doi.org/10.1186/1471-244X-11-65] [PMID: 21504587]
      ] and produces multiple dependent variables: Omission, Commission, Response Time, Variability of Standard Error, and Detectability.
  • To evaluate the tasks described above, we use a total predictive value (TPV) of ≥ 60% as a general criterion for diagnostic efficiency [62Biederman J, Faraone SV, Doyle A, et al. Convergence of the Child Behavior Checklist with structured interview-based psychiatric diagnoses of ADHD children with and without comorbidity. J Child Psychol Psychiatry 1993; 34(7): 1241-51.
    [http://dx.doi.org/10.1111/j.1469-7610.1993.tb01785.x] [PMID: 8245144]
    ]. The altered neuropsychological test was defined by the criterion of Doyle and Biederman [28Doyle AE, Biederman J, Seidman LJ, Weber W, Faraone SV. Diagnostic efficiency of neuropsychological test scores for discriminating boys with and without attention deficit-hyperactivity disorder. J Consult Clin Psychol 2000; 68(3): 477-88.
    [http://dx.doi.org/10.1037/0022-006X.68.3.477] [PMID: 10883564]
    ] that found that the cut-off of 1.0 SD below the controls' mean (1 SD cut-off rule) provided the most efficient diagnostic profile across different tests. We used this cut-off to define which test was altered or not in our patients with ADHD, and we also evaluated how many neuropsychological tests were altered to see if there was a correlation with MPH response.

2.2.2. Clinical Response to Treatment

  • We used the definition of treatment response most used in randomized clinical trials which are based on data from scales filled by parents [29Coghill DR, Banaschewski T, Soutullo C, Cottingham MG, Zuddas A. Systematic review of quality of life and functional outcomes in randomized placebo-controlled studies of medications for attention-deficit/hyperactivity disorder. Eur Child Adolesc Psychiatry 2017; 26(11): 1283-307.
    [http://dx.doi.org/10.1007/s00787-017-0986-y] [PMID: 28429134]
    , 63Huss M, Sikirica V, Hervas A, Newcorn JH, Harpin V, Robertson B. Guanfacine extended release for children and adolescents with attention-deficit/hyperactivity disorder: efficacy following prior methylphenidate treatment. Neuropsychiatr Dis Treat 2016; 112(112): 1085-101.
    [http://dx.doi.org/10.2147/NDT.S94158] [PMID: 27226715]
    -68Findling RL, Adeyi B, Chen G, et al. Clinical Response and Symptomatic Remission in Children Treated With Lisdexamfetamine Dimesylate for Attention-Deficit/Hyperactivity Disorder. CNS Spectr 2010; 15(9): 559-68.
    [http://dx.doi.org/10.1017/S1092852900000535]
    ]. “Complete Response” was defined as the presence of a ≥30% reduction in ADHD-RS-IV.es total score from baseline and a final CGI-S score of 1 or 2 points that lasted at least three months. We defined “Partial Response” as a reduction of <30% in ADHD-RS-IV.es total score from baseline and/or a CGI-S reduction of ≥2 points from baseline but no more than 3 points. “Non-response” was defined as no variations or deterioration in ADHD-RS-IV.es and/or CGI-S scores.
  • We also divided our sample into a two-variable clinical response to treatment based on a CGI-S score filled by the physician in each visit. A “complete response” to MPH was defined by 1 or 2 points at T2 that correspond to an ADHD-RS-IV.es total score reduction from baseline of 30-50% [69Gao H, Zhao Y, Levine L, Allen A. Determining cut-points for clinically meaningful improvement: a receiver operating characteristic characteristic approach. Scientific Proceedings of the 53rd Annual Meeting of the American Academy of Child and Adolescent Psychiatry. Washington, DC. J Am Acad Child Adolesc Psychiatry 2006; 2006: 201., 70Goodman D, Faraone SV, Adler LA, Dirks B, Hamdani M, Weisler R. Interpreting ADHD rating scale scores: linking ADHD rating scale scores and CGI levels in two randomized controlled trials of lisdexamfetamine dimesylate in ADHD. Prim Psychiatry 2010; 17(3): 44-52.].

2.3. Statistical Analyses

Differences in ADHD-RS-IV.es and CGI-S over time were analyzed using two-tailed Τ-test. Correlations between different neuropsychological variables were performed, correlation coefficients Cohen [71Cohen J. Statistical power analysis for the behavioral sciences 1988.], were interpreted as small (r=0.10), medium (r=0.30) or large (r=0.50). All these variables were examined in relation to inattention and hyperactivity symptoms. Correlations, multiple regressions, and logistic regressions analyses were used to investigate socio-demographic, clinical, neuropsychological and psychopharmacological predictors of clinical response. Two-tailed p values <.05 were considered statistically significant. A statistician supervised all analyses and they were conducted using statistical package SPSS (SPSS Inc., Chicago, Illinois) for Windows (v.20.0).

3. RESULTS

3.1. Sample Characteristics

A total of 518 children and adolescents (79.7% boys; mean age (SD): 11.40 (3.30) years old) were included in the study. There were no statistical differences between boys and girls neither in the age of onset (p>.1) nor in diagnostic presentation (DSM-IV subtype). However, the mean age-of-onset in the inattentive subtype (or current presentation on DSM-5) was significantly higher than in the combined group (p=.027). Patients had a mean (SD) follow-up of 33 (22.8) months. According to the DSM-IV-TR, we classified ADHD into two groups: 1. Inattentive subtype (31.7%) and 2. Hyperactive-impulsive and Combined presentations (68.3%). The mean (SD) MPH dose during the dose-maintenance period was 1.21 (0.41) mg/kg/day (Table 1).

Table 1
Sample characteristics in 518 children and adolescents with ADHD.


We analyzed the prevalence of perinatal risk factors in our sample following what is described in the literature (Park et al., 2014). In our sample 8.3% of children were adopted, 10.6% had low weight at birth (<2,500 gr), 15.3% had prenatal nicotine exposure and 10.6% had prenatal alcohol exposure. Among adolescents, only 12% reported occasional alcohol consumption; 7.3% smoked cigarettes and 7.3% had used cannabis (THC) occasionally. Almost half of the patients (48.7%) had co-occurring comorbidities: 23.6% had Oppositional Defiant Disorder (ODD), 21.4% had anxiety symptoms, 10.8% had comorbid depressive symptoms, 2.1% had Bipolar Disorder (BD) and 0.4% had Obsessive-Compulsive Disorder (OCD).

3.2. Neuropsychological Profile

We found that 48.3% of patients showed <1 SD from the mean in at least one neuropsychological test that evaluates EF, 23% showed >1 SD from the mean in one test, and 14.5% showed > 1 SD in two tests (Table 2, Figs. 1 and 2).

  • WISC-IV: Total IQ (mean (SD): 99.31 (12.91)) did not differ significantly (t-test, p>.1) neither between ADHD presentations (inattentive vs. combined) nor in children vs. adolescents. The 79.7% of children had a Total IQ score between 81 and 110, and 19.3% had a Total IQ >111.
  • CPT-II: In the CPT-II test, we found no baseline differences neither between boys vs. girls nor between inattentive vs. combined ADHD presentations, (t-test, p>.1). We found that children were more likely to show higher scores than adolescents in all CPT-II measures (t-scores) (p<.05) with the exception of the Commission Errors.
  • Interference, Stroop Task: The interference effect revealed a significant main effect for sex and age of the onset but not for ADHD presentations. Boys showed higher interference (t=2.16, p=.032) than girls; and this nterference appears to decrease with age (adolescents vs. children) (t=-3.36, p<.001).
Fig. (1)
Proportion of ADHD patients with Altered Neuropsychological Tests.
Considering that the presence of a 1SD away from the average value of the healthy population in any of the test to evaluate the Executive Function (EF) of ADHD patients, we found that a most patients showed no alteration in the different neuropsychological tests. These data suggest that not all children with ADHD suffer from neuropsychological dysfunction.
Note : WISC= Wechsler Intelligence Scale (IQ: intelligence quotient, T-IQ : Total IQ, V-IQ: Verbal IQ, M-IQ: Manipulative IQ, VC: Verbal Comprehension, PR: Perceptual Reasoning, WM: Working Memory, PS: Perceptual Reasoning) CPT-II: Conners’ Continuous Performance Test II (CE: Commission Errors, OE: Omission Errors, Hit RT: Reaction Time,). STROOP: Stroop COLOR WORD Test (I= interference).


Table 2
Neuropsychological profile in 518 children and adolescents with ADHD.


Fig. (2)
Number of Proportion Altered Neuropsychological Tests in ADHD patients.
Neuropsychological Tests evaluated are detailed and described in Fig. (1). We consider “altered test”, according to 1SD cut-off rule (Biederman et al., 1993). In our sample, 48.3% of ADHD patients had no neuropsychological impairment, and only 23% had impairment in one neuropsychological test, and 14.5% had two-test impairment.


3.3. Treatment Response Rates

Efficacy was assessed using the investigator rated ADHD-RS-IV.es and CGI-S scores.

  • ADHD-RS-IV.es and SNAP-IV: At baseline ADHD-RS-IV.es mean severity (SD) was: ADHD-RS-IV.es total score= 29.9 (10.42), inattention subscale score= 17.85 (5.47) and hyperactivity subscale score=12.05 (7.05), and SNAP-IV ODD symptoms´ score was 10.08 (4.47). Patients had a statistically significant improvement in ADHD-RS-IV.es total score from baseline (treatment-naïve) to end point (t=10.67, p<.001), both in girls (t=5.66, p<.001) and in boys (t=9.18, p<.001). We found a significant improvement in both adolescents (t=5.89, p<.001) and children (t=9.05, p<.001). We also found significant improvement in SNAP-IV ODD symptoms from baseline to end point (t=-15.88, p<.001), both in boys (t=-13.66, p<.001) and in girls (t=-8.29, p<.001), in children (t=-11.58, p<.001) and in adolescents (t=-5.89, p<.001) (Table 1).
  • CGI-S: The mean (SD) CGI-S (clinician scored) baseline was 3.85 (0.77). Patients had statistically significant improvement in CGI-S scores from baseline to end point (t=26.13, p<.001), both in girls (t=11.79, p<.001) and in boys (t=23.29, p<.001). We also found a significant improvement in both adolescents (t=16.0, p<.001) and children (t=20.75 p<.001).

According to the definition of response, 37.60% of patients had a “complete response” with a mean MPH dose of 1.23 mg/kg/day, and 35.80% of patients had a “partial response” with a mean MPH dose of 1.18 mg/kg/day. Finally, 26.60% of patients had a “non-response” with a mean MPH dose of 1.25 mg/kg/day. There was no difference in MPH dose in responders vs. non-responders (t-test, p > .1) (ANOVA, p > .1) (Table 3).

Table 3
MPH (mg/kg/day) according to CGI-S response.


3.4. Predictors of Treatment Response

A prediction model was designed considering treatment response according to CGI-S, given than a 30% reduction from baseline in ADHD-RS-IV.es total score corresponds to a CGI-S score of 1 or 2 points [69Gao H, Zhao Y, Levine L, Allen A. Determining cut-points for clinically meaningful improvement: a receiver operating characteristic characteristic approach. Scientific Proceedings of the 53rd Annual Meeting of the American Academy of Child and Adolescent Psychiatry. Washington, DC. J Am Acad Child Adolesc Psychiatry 2006; 2006: 201., 70Goodman D, Faraone SV, Adler LA, Dirks B, Hamdani M, Weisler R. Interpreting ADHD rating scale scores: linking ADHD rating scale scores and CGI levels in two randomized controlled trials of lisdexamfetamine dimesylate in ADHD. Prim Psychiatry 2010; 17(3): 44-52.] (Table 4).

3.4.1. Neuropsychological Predictors

According to the number of altered neuropsychological tests, we observed a gradual decline in the response rate, as the number of neuropsychological altered tests (>1 SD) increased. Treatment response rate (Complete and Partial) was 76.4% in patients with 0 altered tests, 73.1% in patients with 1 altered test, and 62.7% in patients with 2 altered tests. So, in our sample, there was an association between more altered EF-tests, and a worse MPH response (Fig. 3).

When analyzing each test separately, we found that higher baseline Total IQ scores (WISC-IV) and fewer commission errors in the CPT-II predicted a Complete Response (B=0.21, p=.032 B=-0.13, p=.049). None of the other cognitive variables significantly predicted treatment response.

3.4.2. Clinical and Physiological Predictors

When analyzing the role of initial ADHD symptom severity, we found that higher baseline ADHD-RS-IV.es total scores predicted accurately non-response to MPH (B=-0.020, p=.021). More specifically, we found that higher scores in several items significantly predicted (p<.05) a non-response to MPH (“forgets”, “fidgets”, “angry/resentful” and “challenge rules”).

When analyzing the role of the comorbid conditions, we found that comorbid alcohol (B=-1.30, p=.008) and THC use (B=-0.054, p=.017) in adolescence significantly predicted non-response to MPH. Moreover, the presence of comorbid ODD symptoms reported in the SNAP-IV (B=-0.553, p=.032) and depressive symptoms (B=-0.732, p=.026) were predictors of non-response to MPH treatment.

None of the sociodemographic, physiological variables (sex, age of diagnosis, weight, and height), peri-/pre-/postnatal variables (SUD in pregnancy, low birth weight, prematurity, and adoption) significantly predicted treatment response. ADHD subtype presentation (inattentive vs. combined) did not predict treatment response.

Our predictive model indicates that approximately between 5.1% and 6.9% (Cox-Snell R2= .051; Nagelkerke R2 = .069) of the variation in the dependent variable (complete treatment response) is explained by these variables, indicating a small relationship of 5.1% to 6.9% between the predictors and the treatment response.

4. DISCUSSION

Children with ADHD do not all equally respond to MPH treatment [72Dittmann RW, Cardo E, Nagy P, et al. Treatment response and remission in a double-blind, randomized, head-to-head study of lisdexamfetamine dimesylate and atomoxetine in children and adolescents with attention-deficit hyperactivity disorder. CNS Drugs 2014; 28(11): 1059-69.
[http://dx.doi.org/10.1007/s40263-014-0188-9] [PMID: 25038977]
, 73Hautmann C, Rothenberger A, Döpfner M. Daily Symptom Profiles of Children With ADHD Treated With Modified-Release Methylphenidate: An Observational Study. Journal of Attention Disorders 2013; 21(2): 120-8.], and only about 60-70% have an adequate response [23Tamm L, Narad ME, Antonini TN, O’Brien KM, Hawk LW Jr, Epstein JN. Reaction time variability in ADHD: A review. Neurotherapeutics 2012; 9(3): 500-8.
[http://dx.doi.org/10.1007/s13311-012-0138-5] [PMID: 22930417]
, 25Shaw P, Stringaris A, Nigg J, Leibenluft E. Emotion dysregulation in attention deficit hyperactivity disorder. Am J Psychiatry 2014; 171(3): 276-93.
[http://dx.doi.org/10.1176/appi.ajp.2013.13070966] [PMID: 24480998]
, 32Johnston BA, Coghill D, Matthews K, Steele JD. Predicting methylphenidate response in attention deficit hyperactivity disorder: a preliminary study. J Psychopharmacol (Oxford) 2015; 29(1): 24-30.
[http://dx.doi.org/10.1177/0269881114548438] [PMID: 25237119]
, 33Hodgkins P, Shaw M, Coghill D, Hechtman L. Amfetamine and methylphenidate medications for attention-deficit/hyperactivity disorder: complementary treatment options. Eur Child Adolesc Psychiatry 2012; 21(9): 477-92.
[http://dx.doi.org/10.1007/s00787-012-0286-5] [PMID: 22763750]
, 74Ikeda Y, Okuzumi H, Kokubun M. Stroop/reverse-Stroop interference in typical development and its relation to symptoms of ADHD. Res Dev Disabil 2013; 34(8): 2391-8.
[http://dx.doi.org/10.1016/j.ridd.2013.04.019] [PMID: 23714715]
, 75Newcorn JH, Halperin JM, Jensen PS, et al. Symptom profiles in children with ADHD: effects of comorbidity and gender. J Am Acad Child Adolesc Psychiatry 2001; 40(2): 137-46.
[http://dx.doi.org/10.1097/00004583-200102000-00008] [PMID: 11214601]
]. According to ADHD-RS-IV.es scores, in our sample, 56.8% of patients had a positive response (complete or partial), and 75.31% obtained a positive response (partial and complete) on CGI-S scores, that was maintained at the follow-up after 33 (22.8) months. These results correlate with the main findings in the literature [32Johnston BA, Coghill D, Matthews K, Steele JD. Predicting methylphenidate response in attention deficit hyperactivity disorder: a preliminary study. J Psychopharmacol (Oxford) 2015; 29(1): 24-30.
[http://dx.doi.org/10.1177/0269881114548438] [PMID: 25237119]
, 33Hodgkins P, Shaw M, Coghill D, Hechtman L. Amfetamine and methylphenidate medications for attention-deficit/hyperactivity disorder: complementary treatment options. Eur Child Adolesc Psychiatry 2012; 21(9): 477-92.
[http://dx.doi.org/10.1007/s00787-012-0286-5] [PMID: 22763750]
]. According to the multimodal treatment study of ADHD (MTA) [76Hinshaw SP, Carte ET, Sami N, Treuting JJ, Zupan BA. Preadolescent girls with attention-deficit/hyperactivity disorder: II. Neuropsychological performance in relation to subtypes and individual classification. J Consult Clin Psychol 2002; 70(5): 1099-111.
[http://dx.doi.org/10.1037/0022-006X.70.5.1099] [PMID: 12362960]
], we found that children with the most severe levels of ADHD before MPH treatment showed less chance of response than children with less severe ADHD.

As shown in previous studies that examined differences between ADHD subtypes’ response to pharmacological treatment [61Wang LJ, Huang YS, Chiang YL, Hsiao CC, Shang ZY, Chen CK. Clinical symptoms and performance on the Continuous Performance Test in children with attention deficit hyperactivity disorder between subtypes: a natural follow-up study for 6 months. BMC Psychiatry 2011; 11: 65.
[http://dx.doi.org/10.1186/1471-244X-11-65] [PMID: 21504587]
, 77Beery SH, Quay HC, Pelham WE Jr. Differential response to methylphenidate in inattentive and combined subtype ADHD. J Atten Disord 2013.
[http://dx.doi.org/10.1177/1087054712469256] [PMID: 23283758]
-79Barkley RA, DuPaul GJ, McMurray MB. Attention deficit disorder with and without hyperactivity: clinical response to three dose levels of methylphenidate. Pediatrics 1991; 87(4): 519-31.
[PMID: 2011430]
], we did not find a discriminating validity of the effectiveness of MPH by ADHD sub-grouping by DSM-IV-TR (Inattentive vs. Combined subtypes). However, despite not been statistically significant, we found that among all the patients that reached a complete clinical response the doses required by the combined-subgroup of ADHD patients required higher MPH dose than the inattentive subtype group (1.25 [0.42] mg/kg/day) vs. 1.12 [0.37] mg/kg/day respectively). Similar findings were reported by Stein et al. (2003) examining the possibility that inattentive children could respond optimally to lower MPH doses, while combined presentation children could respond best to higher MPH doses [80Stein MA, Sarampote CS, Waldman ID, et al. A dose-response study of OROS methylphenidate in children with attention-deficit/hyperactivity disorder. Pediatrics 2003; 112(5): e404-13.
[http://dx.doi.org/10.1542/peds.112.5.e404] [PMID: 14595084]
].

When comparing clinical response between sex and age, there was no difference in response in boys vs. girls nor in children vs. adolescents, However, although it was not statistically significant, we found that children received higher MPH doses to get a complete response (1.26 [0.42] mg/kg/day) than adolescents (1.15 [0.40] mg/kg/day). Moreover, there were differences in MPH dose in boys vs. girls to reach a complete response. Therefore, the significance of age and sex as predictors of treatment response in ADHD is unclear.

Table 4
Predictors of MPH complete response based on CGI-S.


Fig. (3)
Treatment response (%) reached at end-point (last follow-up visit) according to number of altered neuropshychological tests.
We observed a gradual decline in the response rate, as the number of altered tests increased. The response rate (CGI) in patients with normal executive function (EF) evaluation was 76.4%, while the response rate for patients with 1 or 2 altered tests was 73.1% and 62.7% respectively.
Note : NR: “no-response” PR= “partial response” CR = “complete response”.


The differential response to MPH in ADHD has been linked to a number of comorbidities [42Gray JR, Kagan J. The Challenge of Predicting Which Children with Attention Deficit-Hyperactivity Disorder Will Respond Positively to Methylphenidate. J Appl Dev Psychol 2000; 21(5): 471-89.
[http://dx.doi.org/10.1016/S0193-3973(00)00050-2]
]. Unlike the findings of some studies [38Gadow KD, Nolan EE, Sverd J, Sprafkin J, Schwartz J. Anxiety and depression symptoms and response to methylphenidate in children with attention-deficit hyperactivity disorder and tic disorder. J Clin Psychopharmacol 2002; 22(3): 267-74.
[http://dx.doi.org/10.1097/00004714-200206000-00007] [PMID: 12006897]
, 40Ter-Stepanian M, Grizenko N, Zappitelli M, Joober R. Clinical response to methylphenidate in children diagnosed with attention-deficit hyperactivity disorder and comorbid psychiatric disorders. Can J Psychiatry 2010; 55(5): 305-12.
[http://dx.doi.org/10.1177/070674371005500506] [PMID: 20482957]
, 41Moshe K, Karni A, Tirosh E. Anxiety and methylphenidate in attention deficit hyperactivity disorder: a double-blind placebo-drug trial. Atten Defic Hyperact Disord 2012; 4(3): 153-8.
[http://dx.doi.org/10.1007/s12402-012-0078-2] [PMID: 22622628]
], we found that ADHD children with comorbid depression showed worse MPH response [33Hodgkins P, Shaw M, Coghill D, Hechtman L. Amfetamine and methylphenidate medications for attention-deficit/hyperactivity disorder: complementary treatment options. Eur Child Adolesc Psychiatry 2012; 21(9): 477-92.
[http://dx.doi.org/10.1007/s00787-012-0286-5] [PMID: 22763750]
, 36Chan MH, Leung PW, Ho TP, et al. Neuropsychiatric Disease and Treatment 2017.]. Moreover, we found that the presence of ODD symptoms decreased the probability of positive MPH response in our sample. As noted by Jensen et al. (2001) in a MTA sub-analysis, our results lead to support the evidence that ADHD children with ODD/CD symptoms (but without anxiety disorders) would respond best to pharmacological treatment (with or without behavioral treatments), while children with ODD/CD and anxiety would respond optimally to combined (medication+behavioral) treatments [81Jensen PS, Hinshaw SP, Kraemer HC, et al. ADHD comorbidity findings from the MTA study: comparing comorbid subgroups. J Am Acad Child Adolesc Psychiatry 2001; 40(2): 147-58.
[http://dx.doi.org/10.1097/00004583-200102000-00009] [PMID: 11211363]
]. Most investigations show a negative influence of comorbid SUD in MPH response [35Carpentier PJ, Levin FR. Pharmacological Treatment of ADHD in Addicted Patients: What Does the Literature Tell Us? Harvard review of psychiatry 2017; 25(2): 50-64., 44Tamm L, Trello-Rishel K, Riggs P, et al. Predictors of treatment response in adolescents with comorbid substance use disorder and attention-deficit/hyperactivity disorder. J Subst Abuse Treat 2013; 44(2): 224-30.
[http://dx.doi.org/10.1016/j.jsat.2012.07.001] [PMID: 22889694]
]. Supporting these previous findings, we found that more severe ADHD at baseline and comorbid THC or alcohol use predicted worse response to MPH treatment.

We found that children and adolescents with a higher number of altered neuropsychological tests in the EF assessments had a significantly worse response to MPH treatment (Fig. 3). Total IQ measured by WISC-IV, Commission and Omission errors in the CPT-II and the Interference in the Stroop test has often been related to changes in the MPH treatment in ADHD [82Matsumoto A, Yuji H, Watanabe M. [Life-span development of stroop and reverse-Stroop interference measured using matching responses]. Shinrigaku Kenkyu 2012; 83(4): 337-46.
[http://dx.doi.org/10.4992/jjpsy.83.337] [PMID: 23214083]
]. Regarding how the dysfunction in EF may affect the treatment response in youth with ADHD, Coghill et al (2007) investigated the relationship between MPH response and several neuropsychological measures, in a randomized placebo-controlled trial design [19Coghill DR, Rhodes SM, Matthews K. The neuropsychological effects of chronic methylphenidate on drug-naive boys with attention-deficit/hyperactivity disorder. Biol Psychiatry 2007; 62(9): 954-62.
[http://dx.doi.org/10.1016/j.biopsych.2006.12.030] [PMID: 17543895]
]. They identified 13 variables, as being the most likely to distinguish MPH responders from non-responders: three demographic variables, three clinical variables and various measures from four neuropsychological tasks. They found that poor performance on a ‘delayed matching to sample’ (DMtS) task at baseline was the only pre-treatment correlate of clinical MPH-response. Their data supports previous findings [32Johnston BA, Coghill D, Matthews K, Steele JD. Predicting methylphenidate response in attention deficit hyperactivity disorder: a preliminary study. J Psychopharmacol (Oxford) 2015; 29(1): 24-30.
[http://dx.doi.org/10.1177/0269881114548438] [PMID: 25237119]
] that a comprehensive model of the MPH response would likely rely on a wide range of measures, rather than a single measure. However, to date, there is no objective, biological makers that can robustly predict MPH response in patients with ADHD [46Kim JW, Sharma V, Ryan ND. Predicting Methylphenidate Response in ADHD Using Machine Learning Approaches. Int J Neuropsychopharmacol 2015; 18(11)pyv052
[http://dx.doi.org/10.1093/ijnp/pyv052] [PMID: 25964505]
]. Whilst Hinshaw (2007) and Coghill (2007) identified that age, IQ and symptom severity were possible predictors of MPH response, we found that both baseline ADHD-RS-IV.es symptom severity score (and some specific symptoms), Total-IQ, comorbid disorders (alcohol, THC use, depressive symptoms and ODD symptoms) and the Commission errors could be considered as predictive factors of MPH response [19Coghill DR, Rhodes SM, Matthews K. The neuropsychological effects of chronic methylphenidate on drug-naive boys with attention-deficit/hyperactivity disorder. Biol Psychiatry 2007; 62(9): 954-62.
[http://dx.doi.org/10.1016/j.biopsych.2006.12.030] [PMID: 17543895]
, 76Hinshaw SP, Carte ET, Sami N, Treuting JJ, Zupan BA. Preadolescent girls with attention-deficit/hyperactivity disorder: II. Neuropsychological performance in relation to subtypes and individual classification. J Consult Clin Psychol 2002; 70(5): 1099-111.
[http://dx.doi.org/10.1037/0022-006X.70.5.1099] [PMID: 12362960]
].

At baseline, patients in our sample who had a higher number of altered neuropsychological tests, most severe ADHD symptoms’ score and comorbid depression or alcohol/THC use, showed worse MPH response. On the other hand, patients with higher Total IQ scores and lower Commission errors showed better clinical response to MPH. Further investigations are needed to clarify whether the treatment of comorbid conditions could play a positive role in the MPH response.

5. LIMITATIONS

This study has some important limitations that should be considered for a correct interpretation and generalization of its findings. First of all, the present study did not include any measure related to motivational aspects such as delay aversion and emotional functioning that have also been shown to be predictive of later ADHD symptoms and, as a result, potential predictors of treatment response. Although teacher’s assesments are not essential for diagnosing ADHD or monitoring treatment response [83Bied A, Biederman J, Faraone S. Parent-based diagnosis of ADHD is as accurate as a teacher-based diagnosis of ADHD. Postgrad Med 2017; 129(3): 375-81.
[http://dx.doi.org/10.1080/00325481.2017.1288064] [PMID: 28271921]
], the use of this assessment must be considered in future studies. We also did not include behavioral measures of executive functioning, other than the parameters collected from neuropsychological testing (CPT-II, IQ) based on the fact that literature shows poor correlation between EF impairment in neuropsychological testing and EF assessments using questionnaires [84Toplak ME, Bucciarelli SM, Jain U, Tannock R. Executive functions: performance-based measures and the behavior rating inventory of executive function (BRIEF) in adolescents with attention deficit/hyperactivity disorder (ADHD). Child Neuropsychol 2009; 15(1): 53-72.
[http://dx.doi.org/10.1080/09297040802070929] [PMID: 18608232]
, 85Gioia GA, Isquith PK, Guy S, Kenworthy L. BRIEF: Behavior Rating Inventory of Executive Function professional manual 2000.]. In this study we did not include a normal control group nor blinded raters, thus we could not control placebo effects or rater bias in responders vs. non-responders. However, as we are trying to compare responders vs. non-responders, those two groups could act as controls for each other. We could not find any demographic differences between responders and non-responders. In order to focus mostly on impairment due to ADHD, we excluded children with Total IQ < 80. This is a limitation because maybe these children with lower IQ may have higher neuropsychological deficits and lower rates of response. However, if we had included IQ < 80, the limitation would be that the response or neuropsychological deficits possible differences could be due not to the ADHD but to the low Total IQ.

CONCLUSION

Our findings show that factors related to response inhibition or low impulsivity, and the absence of comorbidity, and lower baseline severity of ADHD may be associated with a better MPH response. On the other hand, the presence of at least one or more than one altered neuropsychological test is associated with worse treatment response. The presence of comorbidities (ODD symptoms, depressive symptoms and alcohol or cannabis use) impact negatively in the treatment response. Furthermore, from the initial interview, the clinician could estimate and adjust the expectations to pharmacological treatment response and have a more frequent follow-up to those patients with a potential “non-responder profile”: children and adolescents with ADHD who have lower Total IQ, ODD symptoms, depressive symptoms and/or substance use, and or altered neuropsychological tests. Comorbidities should be treated, as well as the ADHD, in order to optimize and for a better outcome.

Therefore, there some possible strands of evidence suggesting that MPH response may be, at least partially, predictable using clinical and neuropsychological and clinical data that is often collected within routine clinical practice.

AUTHORS' CONTRIBUTIONS

All authors have made substantial contributions to the conception and design of the work; and the analysis and interpretation of data; and have drafted the work or substantively revised it to have approved this submitted version. All authors agreed both to be personally accountable for the author's own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

Not applicable.

HUMAN AND ANIMAL RIGHTS

Not applicable.

CONSENT FOR PUBLICATION

Not applicable.

AVAILABILITY OF DATA AND MATERIALS

The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.

FUNDING

María Vallejo-Valdivielso, MD has received research funds for her department (non-personal) from Caja Navarra Foundation (CAN), Vasco-Navarra Society of Psychiatry (SVNP), Government of Navarra and Spanish Society of Child and Adolescent Psychiatry (AEPNYA). She has received financial support on continuous scientific education from Shire, Janssen and Lundbeck.

Pilar de Castro-Manglano, MD, PhD has received research funds for her department (non-personal) from Caja Navarra Foundation (CAN), Eli Lilly, Lundbeck and Shire. She has served as Consultant / Advisory Board for: Alicia Koplowitz Foundation, Editorial Médica Panamericana and Eli Lilly. She has served in the Speaker's Bureau / has given talks on Continuous Medical Education (not about a product) for Shire.

Azucena Díez-Suárez, MD, PhD has received research funds for her department (non-personal) from Caja Navarra Foundation (CAN), Otsuka Pharmaceutics, Lundbeck and Shire. She has served as Consultant / Advisory Board for: Alicia Koplowitz Foundation and Editorial Médica Panamericana. She has served in the Speaker's Bureau and has given talks on Continuous Medical Education (not about a product) for Shire.

Juan J. Marín-Méndez, BsC, PhD has received research funds for his department (non-personal) from Caja Navarra Foundation (CAN), Carlos III Health Institute, Government of Navarra, Qpea Foundation and Shire. He has received financial support for continuous scientific education from Shire, Lilly, Rovi, Roche and Pfizer.

César A. Soutullo, MD, PhD has received research funds for his department (non-personal) from Caja Navarra Foundation (CAN), Eli Lilly, Lundbeck, Shire and TEVA. He has served as Consultant / Advisory Board for: Alicia Koplowitz Foundation, Editorial Médica Panamericana, Eli Lilly, EUNETHYDIS (European Network on Hyperkinetic Disorder), Instituto de Salud Carlos III (FIS), NeuroTech Solutions Ltd, Spanish Health Ministry Quality Plan (Clinical Practice Guidelines on TDAH and Clinical Practice Guidelines on Depression), Rubió and Shire. He has served in the Speaker's Bureau / has given talks on Continuous Medical Education (not about a product) for Eli Lilly, Shire, Universidad Internacional Menéndez Pelayo and Universidad Internacional de La Rioja (UNIR). He has received Royalties from: DOYMA, Editorial Médica Panamericana, EUNSA and Mayo Ediciones.

CONFLICT OF INTEREST

The author declares no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

We would like to thank Marta García-Granero for her statistical advice.

REFERENCES

[1] American Psychiatric Association (APA). Diagnostic and statistical manual of mental disorders 2013.
[2] Faraone SV, Asherson P, Banaschewski T, et al. Attention-deficit/hyperactivity disorder. Nat Rev Dis Primers 2015; 1: 15020-0.
[http://dx.doi.org/10.1038/nrdp.2015.20] [PMID: 27189265]
[3] Polanczyk GV, Salum GA, Sugaya LS, Caye A, Rohde LA. Annual research review: A meta-analysis of the worldwide prevalence of mental disorders in children and adolescents. J Child Psychol Psychiatry 2015; 56(3): 345-65.
[http://dx.doi.org/10.1111/jcpp.12381] [PMID: 25649325]
[4] Thomas R, Sanders S, Doust J, Beller E, Glasziou P. Prevalence of attention-deficit/hyperactivity disorder: a systematic review and meta-analysis. Pediatrics 2015; 135(4): e994-e1001.
[http://dx.doi.org/10.1542/peds.2014-3482] [PMID: 25733754]
[5] Thapar A, Cooper M. Attention deficit hyperactivity disorder. Lancet 2016; 387(10024): 1240-50.
[http://dx.doi.org/10.1016/S0140-6736(15)00238-X] [PMID: 26386541]
[6] Biederman J, Faraone SV, Monuteaux MC, Grossbard JR. How informative are parent reports of attention-deficit/hyperactivity disorder symptoms for assessing outcome in clinical trials of long-acting treatments? A pooled analysis of parents’ and teachers’ reports. Pediatrics 2004; 113(6): 1667-71.
[http://dx.doi.org/10.1542/peds.113.6.1667] [PMID: 15173489]
[7] Bledsoe JC, Xiao D, Chaovalitwongse A, et al. Diagnostic Classification of ADHD Versus Control: Support Vector Machine Classification Using Brief Neuropsychological Assessment. J Atten Disord 2016.1087054716649666
[http://dx.doi.org/10.1177/1087054716649666] [PMID: 27231214]
[8] Coghill DR, Seth S, Matthews K. A comprehensive assessment of memory, delay aversion, timing, inhibition, decision making and variability in attention deficit hyperactivity disorder: advancing beyond the three-pathway models. Psychol Med 2014; 44(9): 1989-2001.
[http://dx.doi.org/10.1017/S0033291713002547] [PMID: 24176104]
[9] Sonuga-Barke E, Bitsakou P, Thompson M. Beyond the dual pathway model: evidence for the dissociation of timing, inhibitory, and delay-related impairments in attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2010; 49(4): 345-55.
[http://dx.doi.org/10.1097/00004583-201004000-00009] [PMID: 20410727]
[10] Willcutt EG, Doyle AE, Nigg JT, Faraone SV, Pennington BF. Validity of the executive function theory of attention-deficit/hyperactivity disorder: a meta-analytic review. Biol Psychiatry 2005; 57(11): 1336-46.
[http://dx.doi.org/10.1016/j.biopsych.2005.02.006] [PMID: 15950006]
[11] Sergeant JA, Geurts H, Oosterlaan J. How specific is a deficit of executive functioning for attention-deficit/hyperactivity disorder? Behav Brain Res 2002; 130(1-2): 3-28.
[http://dx.doi.org/10.1016/S0166-4328(01)00430-2] [PMID: 11864714]
[12] Douglas VI. Stop, look and listen: The problem of sustained attention and impulse control in hyperactive and normal children. Can J Behav Sci 1972; 4: 259-82.
[http://dx.doi.org/10.1037/h0082313]
[13] Schoemaker K, Mulder H, Deković M, Matthys W. Executive functions in preschool children with externalizing behavior problems: a meta-analysis. J Abnorm Child Psychol 2013; 41(3): 457-71.
[http://dx.doi.org/10.1007/s10802-012-9684-x] [PMID: 23054130]
[14] Fair DA, Bathula D, Nikolas MA, Nigg JT. Distinct neuropsychological subgroups in typically developing youth inform heterogeneity in children with ADHD. Proc Natl Acad Sci USA 2012; 109(17): 6769-74.
[http://dx.doi.org/10.1073/pnas.1115365109] [PMID: 22474392]
[15] Frazier TW, Demaree HA, Youngstrom EA. Meta-analysis of intellectual and neuropsychological test performance in attention-deficit/hyperactivity disorder. Neuropsychology 2004; 18(3): 543-55.
[http://dx.doi.org/10.1037/0894-4105.18.3.543] [PMID: 15291732]
[16] Seidman LJ. Neuropsychological functioning in people with ADHD across the lifespan. Clin Psychol Rev 2006; 26(4): 466-85.
[http://dx.doi.org/10.1016/j.cpr.2006.01.004] [PMID: 16473440]
[17] Miyake A, Friedman NP, Emerson MJ, Witzki AH, Howerter A, Wager TD. The unity and diversity of executive functions and their contributions to complex “Frontal Lobe” tasks: a latent variable analysis. Cognit Psychol 2000; 41(1): 49-100.
[http://dx.doi.org/10.1006/cogp.1999.0734] [PMID: 10945922]
[18] Barkley RA. Behavioral inhibition, sustained attention, and executive functions: constructing a unifying theory of ADHD. Psychol Bull 1997; 121(1): 65-94.
[http://dx.doi.org/10.1037/0033-2909.121.1.65] [PMID: 9000892]
[19] Coghill DR, Rhodes SM, Matthews K. The neuropsychological effects of chronic methylphenidate on drug-naive boys with attention-deficit/hyperactivity disorder. Biol Psychiatry 2007; 62(9): 954-62.
[http://dx.doi.org/10.1016/j.biopsych.2006.12.030] [PMID: 17543895]
[20] Rhodes SM, Coghill DR, Matthews K. Methylphenidate restores visual memory, but not working memory function in attention deficit-hyperkinetic disorder. Psychopharmacology (Berl) 2004; 175(3): 319-30.
[http://dx.doi.org/10.1007/s00213-004-1833-7] [PMID: 15138760]
[21] Rhodes SM, Coghill DR, Matthews K. Neuropsychological functioning in stimulant-naive boys with hyperkinetic disorder. Psychol Med 2005; 35(8): 1109-20.
[http://dx.doi.org/10.1017/S0033291705004599] [PMID: 16116937]
[22] Kempton S, Vance A, Maruff P, Luk E, Costin J, Pantelis C. Executive function and attention deficit hyperactivity disorder: stimulant medication and better executive function performance in children. Psychol Med 1999; 29(3): 527-38.
[http://dx.doi.org/10.1017/S0033291799008338] [PMID: 10405075]
[23] Tamm L, Narad ME, Antonini TN, O’Brien KM, Hawk LW Jr, Epstein JN. Reaction time variability in ADHD: A review. Neurotherapeutics 2012; 9(3): 500-8.
[http://dx.doi.org/10.1007/s13311-012-0138-5] [PMID: 22930417]
[24] Castellanos FX, Sonuga-Barke EJS, Milham MP, Tannock R. Characterizing cognition in ADHD: beyond executive dysfunction. Trends Cogn Sci (Regul Ed) 2006; 10(3): 117-23.
[http://dx.doi.org/10.1016/j.tics.2006.01.011] [PMID: 16460990]
[25] Shaw P, Stringaris A, Nigg J, Leibenluft E. Emotion dysregulation in attention deficit hyperactivity disorder. Am J Psychiatry 2014; 171(3): 276-93.
[http://dx.doi.org/10.1176/appi.ajp.2013.13070966] [PMID: 24480998]
[26] Sjöwall D, Bohlin G, Rydell AM, Thorell LB. Neuropsychological deficits in preschool as predictors of ADHD symptoms and academic achievement in late adolescence. Child Neuropsychol 2015; 1-18.
[http://dx.doi.org/10.1080/09297049.2015.1063595] [PMID: 26212755]
[27] Nigg JT, Willcutt EG, Doyle AE, Sonuga-Barke EJS. Causal heterogeneity in attention-deficit/hyperactivity disorder: do we need neuropsychologically impaired subtypes? Biol Psychiatry 2005; 57(11): 1224-30.
[http://dx.doi.org/10.1016/j.biopsych.2004.08.025] [PMID: 15949992]
[28] Doyle AE, Biederman J, Seidman LJ, Weber W, Faraone SV. Diagnostic efficiency of neuropsychological test scores for discriminating boys with and without attention deficit-hyperactivity disorder. J Consult Clin Psychol 2000; 68(3): 477-88.
[http://dx.doi.org/10.1037/0022-006X.68.3.477] [PMID: 10883564]
[29] Coghill DR, Banaschewski T, Soutullo C, Cottingham MG, Zuddas A. Systematic review of quality of life and functional outcomes in randomized placebo-controlled studies of medications for attention-deficit/hyperactivity disorder. Eur Child Adolesc Psychiatry 2017; 26(11): 1283-307.
[http://dx.doi.org/10.1007/s00787-017-0986-y] [PMID: 28429134]
[30] Pietrzak RH, Mollica CM, Maruff P, Snyder PJ. Cognitive effects of immediate-release methylphenidate in children with attention-deficit/hyperactivity disorder. Neurosci Biobehav Rev 2006; 30(8): 1225-45.
[http://dx.doi.org/10.1016/j.neubiorev.2006.10.002] [PMID: 17161238]
[31] van der Schaaf ME, Fallon SJ, Ter Huurne N, Buitelaar J, Cools R. Working memory capacity predicts effects of methylphenidate on reversal learning. Neuropsychopharmacology 2013; 38(10): 2011-8.
[http://dx.doi.org/10.1038/npp.2013.100] [PMID: 23612436]
[32] Johnston BA, Coghill D, Matthews K, Steele JD. Predicting methylphenidate response in attention deficit hyperactivity disorder: a preliminary study. J Psychopharmacol (Oxford) 2015; 29(1): 24-30.
[http://dx.doi.org/10.1177/0269881114548438] [PMID: 25237119]
[33] Hodgkins P, Shaw M, Coghill D, Hechtman L. Amfetamine and methylphenidate medications for attention-deficit/hyperactivity disorder: complementary treatment options. Eur Child Adolesc Psychiatry 2012; 21(9): 477-92.
[http://dx.doi.org/10.1007/s00787-012-0286-5] [PMID: 22763750]
[34] Anastopoulos AD, DuPaul GJ, Weyandt LL, et al. 2016.Rates and Patterns of Comorbidity Among First-Year College Students With ADHD
[35] Carpentier PJ, Levin FR. Pharmacological Treatment of ADHD in Addicted Patients: What Does the Literature Tell Us? Harvard review of psychiatry 2017; 25(2): 50-64.
[36] Chan MH, Leung PW, Ho TP, et al. Neuropsychiatric Disease and Treatment 2017.
[37] Abikoff H, McGough J, Vitiello B, et al. Sequential pharmacotherapy for children with comorbid attention-deficit/hyperactivity and anxiety disorders. J Am Acad Child Adolesc Psychiatry 2005; 44(5): 418-27.
[http://dx.doi.org/10.1097/01.chi.0000155320.52322.37] [PMID: 15843763]
[38] Gadow KD, Nolan EE, Sverd J, Sprafkin J, Schwartz J. Anxiety and depression symptoms and response to methylphenidate in children with attention-deficit hyperactivity disorder and tic disorder. J Clin Psychopharmacol 2002; 22(3): 267-74.
[http://dx.doi.org/10.1097/00004714-200206000-00007] [PMID: 12006897]
[39] Pliszka SR. Effect of anxiety on cognition, behavior, and stimulant response in ADHD. J Am Acad Child Adolesc Psychiatry 1989; 28(6): 882-7.
[http://dx.doi.org/10.1097/00004583-198911000-00012] [PMID: 2808258]
[40] Ter-Stepanian M, Grizenko N, Zappitelli M, Joober R. Clinical response to methylphenidate in children diagnosed with attention-deficit hyperactivity disorder and comorbid psychiatric disorders. Can J Psychiatry 2010; 55(5): 305-12.
[http://dx.doi.org/10.1177/070674371005500506] [PMID: 20482957]
[41] Moshe K, Karni A, Tirosh E. Anxiety and methylphenidate in attention deficit hyperactivity disorder: a double-blind placebo-drug trial. Atten Defic Hyperact Disord 2012; 4(3): 153-8.
[http://dx.doi.org/10.1007/s12402-012-0078-2] [PMID: 22622628]
[42] Gray JR, Kagan J. The Challenge of Predicting Which Children with Attention Deficit-Hyperactivity Disorder Will Respond Positively to Methylphenidate. J Appl Dev Psychol 2000; 21(5): 471-89.
[http://dx.doi.org/10.1016/S0193-3973(00)00050-2]
[43] Sullivan MA, Rudnik-Levin F. Attention deficit/hyperactivity disorder and substance abuse. Diagnostic and therapeutic considerations. Ann N Y Acad Sci 2001; 931: 251-70.
[http://dx.doi.org/10.1111/j.1749-6632.2001.tb05783.x] [PMID: 11462745]
[44] Tamm L, Trello-Rishel K, Riggs P, et al. Predictors of treatment response in adolescents with comorbid substance use disorder and attention-deficit/hyperactivity disorder. J Subst Abuse Treat 2013; 44(2): 224-30.
[http://dx.doi.org/10.1016/j.jsat.2012.07.001] [PMID: 22889694]
[45] Denney CB, Rapport MD. Predicting methylphenidate response in children with ADHD: theoretical, empirical, and conceptual models. J Am Acad Child Adolesc Psychiatry 1999; 38(4): 393-401.
[http://dx.doi.org/10.1097/00004583-199904000-00011] [PMID: 10199110]
[46] Kim JW, Sharma V, Ryan ND. Predicting Methylphenidate Response in ADHD Using Machine Learning Approaches. Int J Neuropsychopharmacol 2015; 18(11)pyv052
[http://dx.doi.org/10.1093/ijnp/pyv052] [PMID: 25964505]
[47] American Psychiatric Association (APA). Diagnostic and statistical manual of mental disorders fourth edition, text revision. 2000.
[48] Kaufman J, Birmaher B, Brent D, Rao URN. Schedule for Affective Disorders and Schizophrenia for School Aged Children- Present and Lifetime Version (K-SADS-PL) 1996.
[49] DuPaul GJ, Power TJ, Anastopoulos AD, Reid R. ADHD Rating Scale-IV: Checklists, norms, and clinical interpretation 1998.
[50] Vallejo-Valdivielso M, Soutullo CA, de Castro-Manglano P, Marín-Méndez JJ, Díez-Suárez A. Validation of a Spanish-language version of the ADHD Rating Scale IV in a Spanish sample. Neurologia 2017; 2017
[http://dx.doi.org/10.1016/j.nrl.2017.05.010] [PMID: 28716394]
[51] Swanson J, Nolan W, Pelham W. The SNAP-IV Rating Scale 1992.
[52] Guy W. ECDEU assessment manual for psychopharmacology, revised Rockvill 1976.
[53] Wechsler D. Wechsler Intelligence Scale for Children 2003.
[54] Wechsler D. Wechsler Intelligence Scale for Children 1991.
[55] Stroop J. Studies of interference in serial verbal reaction. J Exp Psychol 1935; 18: 643-62.
[http://dx.doi.org/10.1037/h0054651]
[56] Adleman NE, Menon V, Blasey CM, et al. A developmental fMRI study of the Stroop color-word task. Neuroimage 2002; 16(1): 61-75.
[http://dx.doi.org/10.1006/nimg.2001.1046] [PMID: 11969318]
[57] Zysset S, Müller K, Lohmann G, von Cramon DY. Color-word matching stroop task: separating interference and response conflict. Neuroimage 2001; 13(1): 29-36.
[http://dx.doi.org/10.1006/nimg.2000.0665] [PMID: 11133306]
[58] MacLeod CM. Half a century of research on the Stroop effect: an integrative review. Psychol Bull 1991; 109(2): 163-203.
[http://dx.doi.org/10.1037/0033-2909.109.2.163] [PMID: 2034749]
[59] Golden C. Stroop Color and Word Test: A Manual for Clinical and experimental uses 1978.
[60] Conners CK. Conners’ continuous performance test 1995.
[61] Wang LJ, Huang YS, Chiang YL, Hsiao CC, Shang ZY, Chen CK. Clinical symptoms and performance on the Continuous Performance Test in children with attention deficit hyperactivity disorder between subtypes: a natural follow-up study for 6 months. BMC Psychiatry 2011; 11: 65.
[http://dx.doi.org/10.1186/1471-244X-11-65] [PMID: 21504587]
[62] Biederman J, Faraone SV, Doyle A, et al. Convergence of the Child Behavior Checklist with structured interview-based psychiatric diagnoses of ADHD children with and without comorbidity. J Child Psychol Psychiatry 1993; 34(7): 1241-51.
[http://dx.doi.org/10.1111/j.1469-7610.1993.tb01785.x] [PMID: 8245144]
[63] Huss M, Sikirica V, Hervas A, Newcorn JH, Harpin V, Robertson B. Guanfacine extended release for children and adolescents with attention-deficit/hyperactivity disorder: efficacy following prior methylphenidate treatment. Neuropsychiatr Dis Treat 2016; 112(112): 1085-101.
[http://dx.doi.org/10.2147/NDT.S94158] [PMID: 27226715]
[64] Newcorn JH, Harpin V, Huss M, Johnson M, Ramos-Quiroga JA. Long-term maintenance of efficacy of extended-release guanfacine hydrochloride in children and adolescents with attention-deficit/hyperactivity disorder: double-blind, placebo-controlled, multicentre, Phase 3 randomized withdrawal study 3rd EUNETHYDIS International Conference on ADHD Istanbul, Turkey. 2014.2014.
[65] Coghill D, Banaschewski T, Lecendreux M, et al. European, randomized, phase 3 study of lisdexamfetamine dimesylate in children and adolescents with attention-deficit/hyperactivity disorder. Eur Neuropsychopharmacol 2013; 23(10): 1208-18.
[http://dx.doi.org/10.1016/j.euroneuro.2012.11.012] [PMID: 23332456]
[66] Soutullo C, Banaschewski T, Lecendreux M, et al. A post hoc comparison of the effects of lisdexamfetamine dimesylate and osmotic-release oral system methylphenidate on symptoms of attention-deficit hyperactivity disorder in children and adolescents. CNS Drugs 2013; 27(9): 743-51.
[http://dx.doi.org/10.1007/s40263-013-0086-6] [PMID: 23801529]
[67] Biederman J, Mick E, Surman C, et al. A randomized, 3-phase, 34-week, double-blind, long-term efficacy study of osmotic-release oral system-methylphenidate in adults with attention-deficit/hyperactivity disorder. J Clin Psychopharmacol 2010; 30(5): 549-53.
[http://dx.doi.org/10.1097/JCP.0b013e3181ee84a7] [PMID: 20814332]
[68] Findling RL, Adeyi B, Chen G, et al. Clinical Response and Symptomatic Remission in Children Treated With Lisdexamfetamine Dimesylate for Attention-Deficit/Hyperactivity Disorder. CNS Spectr 2010; 15(9): 559-68.
[http://dx.doi.org/10.1017/S1092852900000535]
[69] Gao H, Zhao Y, Levine L, Allen A. Determining cut-points for clinically meaningful improvement: a receiver operating characteristic characteristic approach. Scientific Proceedings of the 53rd Annual Meeting of the American Academy of Child and Adolescent Psychiatry. Washington, DC. J Am Acad Child Adolesc Psychiatry 2006; 2006: 201.
[70] Goodman D, Faraone SV, Adler LA, Dirks B, Hamdani M, Weisler R. Interpreting ADHD rating scale scores: linking ADHD rating scale scores and CGI levels in two randomized controlled trials of lisdexamfetamine dimesylate in ADHD. Prim Psychiatry 2010; 17(3): 44-52.
[71] Cohen J. Statistical power analysis for the behavioral sciences 1988.
[72] Dittmann RW, Cardo E, Nagy P, et al. Treatment response and remission in a double-blind, randomized, head-to-head study of lisdexamfetamine dimesylate and atomoxetine in children and adolescents with attention-deficit hyperactivity disorder. CNS Drugs 2014; 28(11): 1059-69.
[http://dx.doi.org/10.1007/s40263-014-0188-9] [PMID: 25038977]
[73] Hautmann C, Rothenberger A, Döpfner M. Daily Symptom Profiles of Children With ADHD Treated With Modified-Release Methylphenidate: An Observational Study. Journal of Attention Disorders 2013; 21(2): 120-8.
[74] Ikeda Y, Okuzumi H, Kokubun M. Stroop/reverse-Stroop interference in typical development and its relation to symptoms of ADHD. Res Dev Disabil 2013; 34(8): 2391-8.
[http://dx.doi.org/10.1016/j.ridd.2013.04.019] [PMID: 23714715]
[75] Newcorn JH, Halperin JM, Jensen PS, et al. Symptom profiles in children with ADHD: effects of comorbidity and gender. J Am Acad Child Adolesc Psychiatry 2001; 40(2): 137-46.
[http://dx.doi.org/10.1097/00004583-200102000-00008] [PMID: 11214601]
[76] Hinshaw SP, Carte ET, Sami N, Treuting JJ, Zupan BA. Preadolescent girls with attention-deficit/hyperactivity disorder: II. Neuropsychological performance in relation to subtypes and individual classification. J Consult Clin Psychol 2002; 70(5): 1099-111.
[http://dx.doi.org/10.1037/0022-006X.70.5.1099] [PMID: 12362960]
[77] Beery SH, Quay HC, Pelham WE Jr. Differential response to methylphenidate in inattentive and combined subtype ADHD. J Atten Disord 2013.
[http://dx.doi.org/10.1177/1087054712469256] [PMID: 23283758]
[78] Gorman EB, Klorman R, Thatcher JE, Borgstedt AD. Effects of methylphenidate on subtypes of attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2006; 45(7): 808-16.
[http://dx.doi.org/10.1097/01.chi.0000214191.57993.dd] [PMID: 16832317]
[79] Barkley RA, DuPaul GJ, McMurray MB. Attention deficit disorder with and without hyperactivity: clinical response to three dose levels of methylphenidate. Pediatrics 1991; 87(4): 519-31.
[PMID: 2011430]
[80] Stein MA, Sarampote CS, Waldman ID, et al. A dose-response study of OROS methylphenidate in children with attention-deficit/hyperactivity disorder. Pediatrics 2003; 112(5): e404-13.
[http://dx.doi.org/10.1542/peds.112.5.e404] [PMID: 14595084]
[81] Jensen PS, Hinshaw SP, Kraemer HC, et al. ADHD comorbidity findings from the MTA study: comparing comorbid subgroups. J Am Acad Child Adolesc Psychiatry 2001; 40(2): 147-58.
[http://dx.doi.org/10.1097/00004583-200102000-00009] [PMID: 11211363]
[82] Matsumoto A, Yuji H, Watanabe M. [Life-span development of stroop and reverse-Stroop interference measured using matching responses]. Shinrigaku Kenkyu 2012; 83(4): 337-46.
[http://dx.doi.org/10.4992/jjpsy.83.337] [PMID: 23214083]
[83] Bied A, Biederman J, Faraone S. Parent-based diagnosis of ADHD is as accurate as a teacher-based diagnosis of ADHD. Postgrad Med 2017; 129(3): 375-81.
[http://dx.doi.org/10.1080/00325481.2017.1288064] [PMID: 28271921]
[84] Toplak ME, Bucciarelli SM, Jain U, Tannock R. Executive functions: performance-based measures and the behavior rating inventory of executive function (BRIEF) in adolescents with attention deficit/hyperactivity disorder (ADHD). Child Neuropsychol 2009; 15(1): 53-72.
[http://dx.doi.org/10.1080/09297040802070929] [PMID: 18608232]
[85] Gioia GA, Isquith PK, Guy S, Kenworthy L. BRIEF: Behavior Rating Inventory of Executive Function professional manual 2000.

Endorsements



"Open access will revolutionize 21st century knowledge work and accelerate the diffusion of ideas and evidence that support just in time learning and the evolution of thinking in a number of disciplines."


Daniel Pesut
(Indiana University School of Nursing, USA)

"It is important that students and researchers from all over the world can have easy access to relevant, high-standard and timely scientific information. This is exactly what Open Access Journals provide and this is the reason why I support this endeavor."


Jacques Descotes
(Centre Antipoison-Centre de Pharmacovigilance, France)

"Publishing research articles is the key for future scientific progress. Open Access publishing is therefore of utmost importance for wider dissemination of information, and will help serving the best interest of the scientific community."


Patrice Talaga
(UCB S.A., Belgium)

"Open access journals are a novel concept in the medical literature. They offer accessible information to a wide variety of individuals, including physicians, medical students, clinical investigators, and the general public. They are an outstanding source of medical and scientific information."


Jeffrey M. Weinberg
(St. Luke's-Roosevelt Hospital Center, USA)

"Open access journals are extremely useful for graduate students, investigators and all other interested persons to read important scientific articles and subscribe scientific journals. Indeed, the research articles span a wide range of area and of high quality. This is specially a must for researchers belonging to institutions with limited library facility and funding to subscribe scientific journals."


Debomoy K. Lahiri
(Indiana University School of Medicine, USA)

"Open access journals represent a major break-through in publishing. They provide easy access to the latest research on a wide variety of issues. Relevant and timely articles are made available in a fraction of the time taken by more conventional publishers. Articles are of uniformly high quality and written by the world's leading authorities."


Robert Looney
(Naval Postgraduate School, USA)

"Open access journals have transformed the way scientific data is published and disseminated: particularly, whilst ensuring a high quality standard and transparency in the editorial process, they have increased the access to the scientific literature by those researchers that have limited library support or that are working on small budgets."


Richard Reithinger
(Westat, USA)

"Not only do open access journals greatly improve the access to high quality information for scientists in the developing world, it also provides extra exposure for our papers."


J. Ferwerda
(University of Oxford, UK)

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."


Sean L. Kitson
(Almac Sciences, Northern Ireland)

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."


Hubert Wolterbeek
(Delft University of Technology, The Netherlands)

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."


Alessandro Laviano
(Sapienza - University of Rome, Italy)

"Open access journals are very useful for all scientists as they can have quick information in the different fields of science."


Philippe Hernigou
(Paris University, France)

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."


Fidel Toldrá
(Instituto de Agroquimica y Tecnologia de Alimentos, Spain)

"Open access journals have become a fundamental tool for students, researchers, patients and the general public. Many people from institutions which do not have library or cannot afford to subscribe scientific journals benefit of them on a daily basis. The articles are among the best and cover most scientific areas."


M. Bendandi
(University Clinic of Navarre, Spain)

"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."


Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


Browse Contents




Webmaster Contact: info@benthamopen.net
Copyright © 2020 Bentham Open