Shared and Drug-Specific Effects of Atomoxetine and Methylphenidate on Inhibitory Brain Dysfunction in Medication-Naive ADHD Boys

Cerebral Cortex

Volumn 24, Issue 1, 2014, Pages 174-185

  Cubillo, Ana ^a   Smith, Anna B ^a   Barrett, Nadia ^a   Giampietro, Vincent ^a   Brammer, Michael J ^a   Simmons, Andrew ^a   Rubia, Katya ^a  

^a KING'S COLLEGE LONDON   (United Kingdom)

Author keywords

atomoxetine; attention deficit hyperactivity disorder; functional magnetic resonance imaging; methylphenidate; motor response inhibition; stop task

Indexed keywords

ATOMOXETINE; METHYLPHENIDATE; ADRENERGIC RECEPTOR AFFECTING AGENT; CATECHOLAMINE; CENTRAL STIMULANT AGENT; PROPYLAMINE;

ADOLESCENT; ARTICLE; ATTENTION DEFICIT DISORDER; BRAIN DYSFUNCTION; BRAIN FUNCTION; CHILD; CLINICAL ARTICLE; CONTROLLED STUDY; DRUG EFFECT; FEMALE; FUNCTIONAL MAGNETIC RESONANCE IMAGING; HUMAN; INHIBITORY BRAIN DYSFUNCTION; MALE; PRIORITY JOURNAL; TASK PERFORMANCE; UPREGULATION; ANALYSIS OF VARIANCE; BRAIN; CASE CONTROL STUDY; CONTROLLED CLINICAL TRIAL; CROSSOVER PROCEDURE; DOUBLE BLIND PROCEDURE; IMAGE PROCESSING; INHIBITION (PSYCHOLOGY); INTELLIGENCE TEST; METABOLISM; MOTOR RESPONSE INHIBITION; MOVEMENT (PHYSIOLOGY); NEUROPSYCHOLOGICAL TEST; NUCLEAR MAGNETIC RESONANCE IMAGING; PATHOPHYSIOLOGY; PHYSIOLOGY; PREFRONTAL CORTEX; PSYCHOLOGICAL ASPECT; PSYCHOMOTOR PERFORMANCE; RANDOMIZED CONTROLLED TRIAL; STATISTICAL ANALYSIS; STOP TASK;

ATOMOXETINE; ATTENTION DEFICIT HYPERACTIVITY DISORDER; FUNCTIONAL MAGNETIC RESONANCE IMAGING; METHYLPHENIDATE; MOTOR RESPONSE INHIBITION; STOP TASK;

ADOLESCENT; ADRENERGIC UPTAKE INHIBITORS; ANALYSIS OF VARIANCE; ATTENTION DEFICIT DISORDER WITH HYPERACTIVITY; BRAIN; CASE-CONTROL STUDIES; CATECHOLAMINES; CENTRAL NERVOUS SYSTEM STIMULANTS; CHILD; CROSS-OVER STUDIES; DATA INTERPRETATION, STATISTICAL; DOUBLE-BLIND METHOD; HUMANS; IMAGE PROCESSING, COMPUTER-ASSISTED; INHIBITION (PSYCHOLOGY); INTELLIGENCE TESTS; MAGNETIC RESONANCE IMAGING; MALE; METHYLPHENIDATE; MOVEMENT; NEUROPSYCHOLOGICAL TESTS; PREFRONTAL CORTEX; PROPYLAMINES; PSYCHOMOTOR PERFORMANCE;

EID: 84907227726     PISSN: 10473211     EISSN: 14602199     Source Type: Journal    
DOI: 10.1093/cercor/bhs296     Document Type: Article

References (89)

1. Alderson RM, Rapport MD, Kofler MJ. 2007. Attention-deficit/hyperactivity disorder and behavioral inhibition: a meta-analytic review of the stop-signal paradigm. J Abnorm Child Psychol. 35:745-758.
2. th ed. Washington, DC: American Psychiatric Association. Text Revision.
3. Aron AR, Durston S, Eagle DM, Logan GD, Stinear CM, Stuphorn V. 2007. Converging evidence for a fronto-basal-ganglia network for inhibitory control of action and cognition. J Neurosci. 27:11860-11864.
4. Aron AR, Fletcher PC, Bullmore ET, Sahakian BJ, Robbins TW. 2003. Stop-signal inhibition disrupted by damage to right inferior frontal gyrus in humans. Nat Neurosci. 6:115-116.
5. Aron AR, Poldrack RA. 2006. Cortical and subcortical contributions to stop signal response inhibition: role of the subthalamic nucleus. J Neurosci. 26:2424-2433.
6. Aron AR, Robbins TW, Poldrack RA. 2004. Inhibition and the right inferior frontal cortex. Trends Cogn Sci. 8:170-177.
7. Aston-Jones G, Cohen JD. 2005. An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance. Annu Rev Neurosci. 28:403-450.
8. Bedard AC, Ickowicz A, Logan GD, Hogg-Johnson S, Schachar R, Tannock R. 2003. Selective inhibition in children with attention-deficit hyperactivity disorder off and on stimulant medication. J Abnorm Child Psychol. 31:315-327.
9. Behrmann M, Geng JJ, Shomstein S. 2004. Parietal cortex and attention. Curr Opin Neurobiol. 14:212-217.
10. Berridge CW, Waterhouse BD. 2003. The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes. Brain Res Brain Res Rev. 42:33-84.
11. Brammer MJ, Bullmore ET, Simmons A, Williams SC, Grasby PM, Howard RJ, Woodruff PW, Rabe-Hesketh S. 1997. Generic brain activation mapping in functional magnetic resonance imaging: a nonparametric approach. Magn Res Imaging. 15:763-770.
12. Bridgett DJ, Walker ME. 2006. Intellectual functioning in adults with ADHD: a meta-analytic examination of full scale IQ differences between adults with and without ADHD. Psychol Assess. 18:1-14.
13. Bullmore E, Long C, Suckling J, Fadili J, Calvert G, Zelaya F, Carpenter TA, Brammer M. 2001. Colored noise and computational inference in neurophysiological (fMRI) time series analysis: resampling methods in time and wavelet domains. Hum Brain Mapp. 12:61-78.
14. Bullmore ET, Brammer MJ, Rabe-Hesketh S, Curtis VA, Morris RG, Williams SC, Sharma T, McGuire PK. 1999. Methods for diagnosis and treatment of stimulus-correlated motion in generic brain activation studies using fMRI. Hum Brain Mapp. 7:38-48.
15. Bullmore ET, Suckling J, Overmeyer S, Rabe-Hesketh S, Taylor E, Brammer MJ. 1999. Global, voxel, and cluster tests, by theory and permutation, for a difference between two groups of structural MR images of the brain. IEEE Trans Med Imaging. 18:32-42.
16. Bymaster FP, Katner JS, Nelson DL, Hemrick-Luecke SK, Threlkeld PG, Heiligenstein JH, Morin SM, Gehlert DR, Perry KW. 2002. Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology. 27:699-711.
17. Chamberlain SR, Del Campo N, Dowson J, Muller U, Clark L, Robbins TW, Sahakian BJ. 2007. Atomoxetine improved response inhibition in adults with attention deficit/hyperactivity disorder. Biol Psychiatry. 62:977-984.
18. Chamberlain SR, Hampshire A, Muller U, Rubia K, Del Campo N, Craig K, Regenthal R, Suckling J, Roiser JP, Grant JE et al. 2009.
19. Atomoxetine modulates right inferior frontal activation during inhibitory control: a pharmacological functional magnetic resonance imaging study. Biol Psychiatry. 65:550-555.
20. Chambers CD, Bellgrove MA, Stokes MG, Henderson TR, Garavan H, Robertson IH, Morris AP, Mattingley JB. 2006. Executive "brake failure" following deactivation of human frontal lobe. J Cogn Neurosci. 18:444-455.
21. Chambers CD, Garavan H, Bellgrove MA. 2009. Insights into the neural basis of response inhibition from cognitive and clinical neuroscience. Neurosci Biobehav Rev. 33:631-646.
22. Chan YP, Swanson JM, Soldin SS, Thiessen JJ, Macleod SM, Logan W. 1983. Methylphenidate hydrochloride given with or before breakfast: II. Effects on plasma concentration of methylphenidate and ritalinic acid. Pediatrics. 72:56-59.
23. Chevrier AD, Noseworthy MD, Schachar R. 2007. Dissociation of response inhibition and performance monitoring in the stop signal task using event-related fMRI. Hum Brain Mapp. 28:1347-1358.
24. Conners CK, Sitarenios G, Parker JDA, Epstein JN. 1998. Revision and restandardization of the Conners Teacher Rating Scale (CTRS-R): factor structure, reliability, and criterion validity. J Abnorm Child Psychol. 26:279-291.
25. Corbetta M, Shulman GL. 2002. Control of goal-directed and stimulus-driven attention in the brain. Nat Rev Neurosci. 3:201-215.
26. Costa A, Riedel M, Pogarell O, Menzel-Zelnitschek F, Schwarz M, Reiser M, Moller HJ, Rubia K, Meindl T, Ettinger U. Forthcoming 2013. Methylphenidate effects on neural activity during response inhibition in healthy humans. Cereb Cortex. 23:1179-1189.
27. Cubillo A, Halari R, Smith A, Taylor E, Rubia K. 2012. A review of fronto-striatal and frontocortical brain abnormalities in children and adults with Attention Deficit Hyperactivity Disorder (ADHD) and new evidence for dysfunction in adults with ADHD during motivation and attention. Cortex. 48:194-215.
28. Del Campo N, Chamberlain SR, Sahakian BJ, Robbins TW. 2011. The roles of dopamine and noradrenaline in the pathophysiology and treatment of attention-deficit/hyperactivity disorder. Biol Psychiatry. 69:e145-e157.
29. Dennis M, Francis DJ, Cirino PT, Schachar R, Barnes MA, Fletcher JM. 2009. Why IQ is not a covariate in cognitive studies of neurodevelopmental disorders. J Int Neuropsychol Soc. 15:331-343.
30. Derrfuss J, Brass M, Neumann J, von Cramon DY. 2005. Involvement of the inferior frontal junction in cognitive control: meta-analyses of switching and Stroop studies. Hum Brain Mapp. 25:22-34.
31. DeVito EE, Blackwell AD, Clark L, Kent L, Dezsery AM, Turner DC, Aitken MR, Sahakian BJ. 2009. Methylphenidate improves response inhibition but not reflection-impulsivity in children with attention defi cit hyperactivity disorder (ADHD). Psychopharmacology (Berl). 202:531-539.
32. Downar J, Crawley AP, Mikulis DJ, Davis KD. 2002. A cortical network sensitive to stimulus salience in a neutral behavioral context across multiple sensory modalities. J Clin Neurophysiol. 87:615-620.
33. Epstein JN, Casey BJ, Tonev ST, Davidson MC, Reiss AL, Garrett A, Hinshaw SP, Greenhill LL, Glover G, Shafritz KM et al. 2007. ADHD- and medication-related brain activation effects in concordantly affected parent-child dyads with ADHD. J Child Psychol Psychiatry. 48:899-913.
34. Frodl T, Skokauskas N. 2012. Meta-analysis of structural MRI studies in children and adults with attention deficit hyperactivity disorder indicates treatment effects. Acta Psychiatr Scand. 125:114-126.
35. Fusar-Poli P, Rubia K, Rossi G, Sartori G, Balottin U. 2012. Striatal dopamine transporter alterations in ADHD: pathophysiology or adaptation to psychostimulants? A meta-analysis. Am J Psychiatry. 169:264-272.
36. Gallezot JD, Weinzimmer D, Nabulsi N, Lin SF, Fowles K, Sandiego C, McCarthy TJ, Maguire RP, Carson RE, Ding YS. 2011. Evaluation of [(11)C]MRB for assessment of occupancy of norepinephrine transporters: studies with atomoxetine in non-human primates. Neuroimage. 56:268-279.
37. Goghari VM, MacDonald AW 3rd. 2009. The neural basis of cognitive control: response selection and inhibition. Brain Cogn. 71:72-83.
38. Goldberg D, Murray R. 2002. Maudsley handbook of practical psychiatry. Oxford: Oxford University Press.
39. Goodman R, Scott S. 1999. Comparing the strengths and difficulties questionnaire and the child behavior checklist: is small beautiful? J Abnorm Child Psychol. 27:17-24.
40. Graf H, Abler B, Freudenmann R, Beschoner P, Schaeffeler E, Spitzer M, Schwab M, Gron G. 2011. Neural correlates of error monitoring modulated by atomoxetine in healthy volunteers. Biol Psychiatry. 69:890-897.
41. Greenhill LL, Swanson JM, Vitiello B, Davies M, Clevenger W, Wu M, Arnold LE, Abikoff HB, Bukstein OG, Conners CK et al. 2001. Impairment and deportment responses to different methylphenidate doses in children with ADHD: the MTA titration trial. J Am Acad Child Adolesc Psychiatry. 40:180-187.
42. Haber SN. 2003. The primate basal ganglia: parallel and integrative networks. J Chem Neuroanat. 26:317-330.
43. Hannestad J, Gallezot JD, Planeta-Wilson B, Lin SF, Williams WA, van Dyck CH, Malison RT, Carson RE, Ding YS. 2010. Clinically relevant doses of methylphenidate significantly occupy norepinephrine transporters in humans in vivo. Biol Psychiatry. 68:854-860.
44. Hanwella R, Senanayake M, de Silva V. 2011. Comparative efficacy and acceptability of methylphenidate and atomoxetine in treatment of attention deficit hyperactivity disorder in children and adolescents: a meta-analysis. BMC Psychiatry. 11:176-184.
45. Hazell PL, Kohn MR, Dickson R, Walton RJ, Granger RE, van Wyk GW. 2010. Core ADHD symptom improvement with atomoxetine versus methylphenidate: a direct comparison meta-analysis. J Atten Disord. 15:674-683.
46. Konrad K, Gunther T, Hanisch C, Herpertz-Dahlmann B. 2004. Differential effects of methylphenidate on attentional functions in children with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 43:191-198.
47. Konrad K, Neufang S, Fink GR, Herpertz-Dahlmann B. 2007. Long-term effects of methylphenidate on neural networks associated with executive attention in children with ADHD: results from a longitudinal functional MRI study. J Am Acad Child Adolesc Psychiatry. 46:1633-1641.
48. Lijffijt M, Kenemans JL, ter Wal A, Quik EH, Kemner C, Westenberg H, Verbaten MN, van Engeland H. 2006. Dose-related effect of methylphenidate on stopping and changing in children with attention-deficit/hyperactivity disorder. Eur Psychiatry. 21:544-547.
49. Matthews JN, Altman DG. 1996. Statistics notes. Interaction 2: compare effect sizes not P values. BMJ. 313:808.
50. Miller G, Chapman J. 2001. Misunderstanding analysis of covariance. J Abnorm Psychol. 110:40-48.
51. Montoya A, Hervas A, Cardo E, Artigas J, Mardomingo MJ, Alda JA, Gastaminza X, Garcia-Polavieja MJ, Gilaberte I, Escobar R. 2009. Evaluation of atomoxetine for first-line treatment of newly diagnosed, treatment-naive children and adolescents with attention deficit/hyperactivity disorder. Curr Med Res Opin. 25:2745-2754.
52. Nakao T, Radua J, Rubia K, Mataix-Cols D. 2011. Gray matter volume abnormalities in ADHD and the effects of stimulant medication: voxel-based meta-analysis. Am J Psychiatry. 168:1154-1163.
53. Nandam LS, Hester R, Wagner J, Cummins TD, Garner K, Dean AJ, Kim BN, Nathan PJ, Mattingley JB, Bellgrove MA. 2011. Methylphenidate but not atomoxetine or citalopram modulates inhibitory control and response time variability. Biol Psychiatry. 69:902-904.
54. Nee DE, Wager TD, Jonides J. 2007. Interference resolution: insights from a meta-analysis of neuroimaging tasks. Cogn Affect Behav Neurosci. 7:1-17.
55. Pauls AM, O'Daly OG, Rubia K, Riedel WJ, Williams SC, Mehta MA. Forthcoming 2012. Methylphenidate effects on prefrontal functioning during attentional-capture and response inhibition. Biol Psychiatry. 72:142-149.
56. Peterson BS, Potenza MN, Wang Z, Zhu H, Martin A, Marsh R, Plessen KJ, Yu S. 2009. An FMRI study of the effects of psychostimulants on default-mode processing during Stroop task performance in youths with ADHD. Am J Psychiatry. 166:1286-1294.
57. Pliszka SR, Glahn DC, Semrud-Clikeman M, Franklin C, Perez R, Xiong JJ. 2006. Neuroimaging of inhibitory control areas in children with attention deficit hyperactivity disorder who were treatment naive or in long-term treatment. Am J Psychiatry. 163:1052-1060.
58. Rubia K. 2011. "Cool" inferior fronto-striatal dysfunction in attention-deficit hyperactivity disorder (ADHD) versus "hot" ventromedial orbitofronto-limbic dysfunction in conduct disorder: a review. Biol Psychiatry. 69:e69-e87.
59. Rubia K, Cubillo A, Smith AB, Woolley J, Heyman I, Brammer MJ. 2010. Disorder-specific dysfunction in right inferior prefrontal cortex during two inhibition tasks in boys with attention-deficit hyperactivity disorder compared to boys with obsessive-compulsive disorder. Hum Brain Mapp. 31:287-299.
60. Rubia K, Halari R, Christakou A, Taylor E. 2009. Impulsiveness as a timing disturbance: neurocognitive abnormalities in attention-deficit hyperactivity disorder during temporal processes and normalization with methylphenidate. Philos Trans R Soc Lond B Biol Sci. 364:1919-1931.
61. Rubia K, Halari R, Cubillo A, Mohammad AM, Brammer M, Taylor E. 2011. Methylphenidate normalises fronto-striatal underactivation during interference inhibition in medication-naive children with attention-deficit hyperactivity disorder. Neuropsychopharmacology. 36:1575-1586.
62. Rubia K, Halari R, Cubillo A, Mohammad M, Taylor E. 2009. Methylphenidate normalises activation and functional connectivity deficits in attention and motivation networks in medication-naïve children with ADHD during a rewarded continuous performance task. Neuropharmacology. 57:640-652.
63. Rubia K, Halari R, Mohammad AM, Taylor E, Brammer M. 2011. Methylphenidate normalises fronto-cingulate underactivation during error processing in attention-defi cit hyperactivity disorder. Biol Psychiatry. 70:255-262.
64. Rubia K, Halari R, Smith AB, Mohammed M, Scott S, Giampietro V, Taylor E, Brammer MJ. 2008. Dissociated functional brain abnormalities of inhibition in boys with pure conduct disorder and in boys with pure attention deficit hyperactivity disorder. Am J Psychiatry. 165:889-897.
65. Rubia K, Overmeyer S, Taylor E, Brammer M, Williams SC, Simmons A, Bullmore ET. 1999. Hypofrontality in attention deficit hyperactivity disorder during higher-order motor control: a study with functional MRI. Am J Psychiatry. 156:891-896.
66. Rubia K, Smith AB, Brammer MJ, Toone B, Taylor E. 2005. Abnormal brain activation during inhibition and error detection in medication-naive adolescents with ADHD. Am J Psychiatry. 162:1067-1075.
67. Rubia K, Smith AB, Brammer MJ, Taylor E. 2003. Right inferior prefrontal cortex mediates response inhibition while mesial prefrontal cortex is responsible for error detection. Neuroimage. 20:351-358.
68. Rubia K, Smith AB, Brammer MJ, Taylor E. 2007. Temporal lobe dysfunction in medication-naive boys with attention-deficit/hyperactivity disorder during attention allocation and its relation to response variability. Biol Psychiatry. 62:999-1006.
69. Rubia K, Smith A, Halari R, Matukura F, Mohammad M, Taylor E, Brammer M. 2009. Disorder-specific dissociation of orbitofrontal dysfunction in boys with pure Conduct disorder during reward and ventrolateral prefrontal dysfunction in boys with pure attention-deficit/hyperactivity disorder during sustained attention. Am J Psychiatry. 166:83-94.
70. Rubia K, Smith AB, Taylor E, Brammer M. 2007. Linear age-correlated functional development of right inferior fronto-striato-cerebellar networks during response inhibition and anterior cingulate during error-related processes. Hum Brain Mapp. 28:1163-1177.
71. Rutter M, Bailey A, Berument S, LeCouteur A, Lord C, Pickles A, editors. 2003. Social Communication Questionnaire (SCQ). Los Angeles, (CA): Western Psychological Services.
72. Scheres A, Oosterlaan J, Swanson J, Morein-Zamir S, Meiran N, Schut H, Vlasveld L, Sergeant JA. 2003. The effect of methylphenidate on three forms of response inhibition in boys with AD/HD. J Abnorm Child Psychol. 31:105-120.
73. Shafritz KM, Marchione KE, Gore JC, Shaywitz SE, Shaywitz BA. 2004. The effects of methylphenidate on neural systems of attention in attention deficit hyperactivity disorder. Am J Psychiatry. 161:1990-1997.
74. Sharp DJ, Bonnelle V, De Boissezon X, Beckmann CF, James SG, Patel MC, Mehta MA. 2010. Distinct frontal systems for response inhibition, attentional capture, and error processing. Proc Natl Acad Sci USA. 107:6106-6111.
75. Simmons A, Moore E, Williams SC. 1999. Quality control for functional magnetic resonance imaging using automated data analysis and Shewhart charting. Magn Reson Med. 41:1274-1278.
76. Smith A, Taylor E, Brammer M, Toone B, Rubia K. 2006. Task-specific hypoactivation in prefrontal and temporoparietal brain regions during motor inhibition and task switching in medication-naive children and adolescents with attention deficit hyperactivity disorder. Am J Psychiatry. 163:1044-1051.
77. Stevens MC, Kiehl KA, Pearlson GD, Calhoun VD. 2009. Brain network dynamics during error commission. Hum Brain Mapp. 30:24-37.
78. Stevens MC, Pearlson GD, Kiehl KA. 2007. An fMRI auditory oddball study of combined-subtype attention deficit hyperactivity disorder. Am J Psychiatry. 164:1737-1749.
79. Swick D, Ashley V, Turken AU. 2008. Left inferior frontal gyrus is critical for response inhibition. BMC Neurosci. 9:102-113.
80. Tamm L, Menon V, Reiss AL. 2006. Parietal attentional system aberrations during target detection in adolescents with attention deficit hyperactivity disorder: event-related fMRI evidence. Am J Psychiatry. 163:1033-1043.
81. Tannock R, Schachar RJ, Carr RP, Chajczyk D, Logan GD. 1989. Effects of methylphenidate on inhibitory control in hyperactive children. J Abnorm Child Psychol. 17:473-491.
82. Thirion B, Pinel P, Meriaux S, Roche A, Dehaene S, Poline JB. 2007. Analysis of a large fMRI cohort: statistical and methodological issues for group analyses. Neuroimage. 35:105-120.
83. Tucker DM, Williamson PA. 1984. Asymmetric neural control systems in human self-regulation. Psychol Rev. 91:185-215.
84. Vaidya CJ, Austin G, Kirkorian G, Ridlehuber HW, Desmond JE, Glover GH, Gabrieli JDE. 1998. Selective effects of methylphenidate in attention deficit hyperactivity disorder: a functional magnetic resonance study. Proc Natl Acad Sci USA. 95:14494-14499.
85. van Wyk GW, Hazell PL, Kohn MR, Granger RR, Walton RJ. 2012. How oppositionality, inattention, and hyperactivity affect response to atomoxetine versus methylphenidate: a meta-analysis. J Atten Disord. 16:314-324.
86. Volkow ND, Wang GJ, Fowler JS, Gatley SJ, Logan J, Ding YS, Hitzemann R, Pappas N. 1998. Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate. Am J Psychiatry. 155:1325-1331.
87. Wechsler D. 1999. Wechsler Abbreviated Scale of Intelligence. San Antonio, Texas: The Psychological Corporation.
88. Weissman DH, Woldorff MG. 2005. Hemispheric asymmetries for different components of global/local attention occur in distinct temporo-parietal loci. Cereb Cortex. 15:870-876.
89. Witcher JW, Long A, Smith B, Sauer JM, Heilgenstein J, Wilens T, Spencer T, Biederman J. 2003. Atomoxetine pharmacokinetics in children and adolescents with attention deficit hyperactivity disorder. J Child Adolesc Psychopharmacol. 13:53-63.