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Methylphenidate But Not Atomoxetine or Citalopram

Modulates Inhibitory Control and Response Time
Variability
L. Sanjay Nandam, Robert Hester, Joe Wagner, Tarrant D.R. Cummins, Kelly Garner, Angela J. Dean,
Bung Nyun Kim, Pradeep J. Nathan, Jason B. Mattingley, and Mark A. Bellgrove
Background: Response inhibition is a prototypical executive function of considerable clinical relevance to psychiatry. Nevertheless, our
understanding of its pharmacological modulation remains incomplete.
Methods: We used a randomized, double-blind, placebo-controlled, crossover design to examine the effect of an acute dose of methyl-
phenidate (MPH) (30 mg), atomoxetine (ATM) (60 mg), citalopram (CIT) (30 mg), and placebo (PLAC) (dextrose) on the stop signal inhibition
task in 24 healthy, right-handed men 18 –35 years of age. Participants performed the task under each of the four drug conditions across four
consecutive sessions.
Results: Methylphenidate led to a reduction in both response time variability and stop-signal reaction time (SSRT), indicating enhanced
response inhibition compared with all other drug conditions. Crucially, the enhancement of response inhibition by MPH occurred without
concomitant changes in overall response speed, arguing against a simple enhancement of processing speed. We found no significant
differences between ATM and PLAC, CIT and PLAC, or ATM and CIT for either response time variability or SSRT.
Conclusions: An acute dose of MPH but not ATM or CIT was able to improve SSRT and reduce response time variability in nonclinical
participants. Improvements in response inhibition and response variability might underlie the reported clinical benefits of MPH in disorders
such as attention-deficit/hyperactivity disorder.
Key Words: Atomoxetine, citalopram, methylphenidate, response
are respected, an index of the speed of inhibition can be calculated, Reaction time tasks, including the stop-signal task, also allow Theprocessesthatinhibitunwantedbehaviorandmaintain measurementofbehavioralvariability,measuredastheSDofreac- consistent task performance are impaired in several psychiat- tion times to the go signal. Increased variability is thought to arise ric conditions, including schizophrenia obsessive compul- from both moment-to-moment fluctuations in attentional control sive disorder and attention-deficit/hyperactivity disorder and from more gradual drifts in performance that might result from (ADHD) Significant controversy exists regarding their precise neurochemical basis, despite the relevance of response inhibition Here we sought to determine the influence of three agents that and variability to psychiatry and their potential for pharmacological are used in the management of ADHD (MPH, ATM) and obsessive treatment. Here we used a within-subjects design to examine the compulsive disorder (CIT) on behavioral measures of response inhi- influence of an acute dose of methylphenidate (MPH), atomoxetine bition. A randomized, double-blind, placebo-controlled, crossover (ATM), citalopram (CIT), or PLAC on measures of inhibitory control design was used to study the effects of an acute dose of MPH (30 mg), ATM (60 mg), CIT (30 mg), and PLAC (dextrose) on SSRT and Response inhibition has been studied in cognitive neuroscience behavioral variability in healthy subjects.
with paradigms such as the stop-signal task. This task requires the Methods and Materials
countermanding or cancelation of a prepotent “go” response uponpresentation of an infrequent “stop” signal. Stop-signal inhibition Participants
can be viewed as a race between two competing “go” and “stop” Twenty-four healthy right-handed, nonclinical Caucasian male processes. By introducing a delay between the presentation of the participants, 18 –35 years of age, were recruited. Additional details go and any subsequent stop signal, one can bias the outcome of the regarding the recruitment and screening procedures can be found race. When the theoretical assumptions underlying this race model Drug Administration
From the University of Queensland (LSN, JW, TDRC, KG, AJD, BNK, JBM, MAB), Participants were tested on the same day and time across 4 Queensland Brain Institute and School of Psychology; Prince CharlesHospital (LSN), Brisbane; University of Melbourne (RH), Department of consecutive weeks in a double-blind manner. On each occasion a Psychology, Parkville; Monash University (PJN), School of Psychology, single blue gelatine capsule containing MPH 30 mg, ATM 60 mg, CIT Psychiatry and Psychological Medicine, Clayton, Australia; Seoul Na- 30 mg, or PLAC (dextrose) was ingested with water. Participants tional University (BNK), Division of Child and Adolescent Psychiatry, performed the stop-signal reaction time task from min ϩ150 to Department of Neuropsychiatry, College of Medicine, Seoul, Korea; and ϩ180 after drug administration. There was no significant drug ϫ The University of Cambridge (PJN), Department of Psychiatry, Cam- time interactions for either blood pressure or subjective side effect Address correspondence to Mark Bellgrove, Ph.D., Queensland Brain Instit- ute, The University of Queensland, 4072 Brisbane, Australia. E-mail: Stop-Signal Paradigm
The SSRT was derived as the mean reaction time to go-stimuli Received Jun 30, 2010; revised Nov 8, 2010; accepted Nov 8, 2010.
(mean reaction time [MRT]) minus the stop signal delay for the 50% Table 1. Mean SSRT and MRT and Stop-Signal Accuracy as a Function of Drug Condition
Methylphenidate 30 mg (MPH); atomoxetine 60 mg (ATM); citalopram 30 mg (CIT); placebo (PLAC). SSRT, stop- signal reaction time (msec); MRT, mean correct “go” reaction time (msec); % stop, percentage of successful inhibitionson stop trials; ICV, intra-individual coefficient of variation (SD of MRT/MRT).
inhibition threshold (SSRT ϭ MRT Ϫ stop-signal delay) The Methylphenidate is a widely used stimulant medication for the intraindividual coefficient of variation [ICV: SD Go RT/MRT] was also treatment of ADHD, with clinical response rates of approximately calculated, which provides a measure of response variability, ad- 70%. Although MPH is often viewed as a dopaminergic agent, its justed for the influence of response speed pharmacology suggests effects on both dopamine (DA) and nor-adrenaline (NA). Within the striatum, MPH acts to inhibit the re- uptake of DA by blockade of the dopamine transporter (DAT) The increase in DA occasioned by DAT blockade likely modulates There was a significant effect of drug condition on SSRT activity within the circuits of the basal ganglia, particularly via D2 [F (3,66) ϭ 5.83, p Ͻ .01]. Methylphenidate led to a reduction in and D1 receptors within the indirect and direct pathways, respec- SSRTs, indicating enhanced response inhibition compared with all tively. However, MPH increases both DA and NA at doses that en- other drug conditions. Post hoc least significant difference testsrevealed significant differences between MPH and PLAC (p Ͻ .001; hance prefrontally dependent executive functions such as working d ϭ .65) and MPH and CIT (p Ͻ .01; d ϭ .62) and between MPH and memory This effect is likely mediated via blockade of the ATM (p ϭ .05, d ϭ .42) There were no significant differ- noradrenaline transporter (NET), because DAT is sparse in prefron- ences between ATM and PLAC (p ϭ .1; d ϭ .32) or between ATM and tal cortex At the receptor level, the cognitive enhancing effects CIT (p ϭ .2; d ϭ .26).
of MPH in rat prefrontal cortex seem to be mediated by its effects on Crucially, the selective enhancement of response inhibition by MPH occurred without concomitant changes in response speed, Pharmacological work in rodents has shown that, although ATM because there was no main effect of drug condition on MRT selectively inhibits NET in prefrontal cortex, there is a resultant [F (3,66) ϭ .54, p ϭ .65]. This suggests that MPH was able to specifi- threefold increase in both NA and DA levels, without any concomi- cally improve action cancelation without simply increasing overall tant change in serotonin However, within the striatum NET is motor speed. A conservative reanalysis of the SSRT data with MRT as sparse, and ATM has only a limited ability to modulate catechol- a covariate confirmed the significant effect of drug condition on amine levels. Although ATM and MPH have similar effects on both SSRT [p ϭ .002]. There was no main effect of drug condition on DA and NA in prefrontal cortex, a key difference is conferred by the stop-signal accuracy [F (3,66) ϭ 1.35, p ϭ .27] ability of MPH to selectively increase DA within the striatum Significant main effects of drug condition were found for the Current models of behavioral inhibition emphasize the interac- intraindividual coefficient of variation [F (3,66) ϭ 5.76, p ϭ .001].
tion of prefrontal and basal ganglia circuits Specifically, Methylphenidate led to a reduction in response time variability that prefrontal circuits might provide a top-down, stimulus-driven input was significantly different from all other conditions (all p values Ͻ to the basal ganglia, signaling the need for enhanced behavioral .05, corrected) No other drug comparisons of variability control. Both MPH and ATM are well-placed to exert a neuromodu- latory influence over the prefrontal cortex, and indeed functional Because MPH enhanced both SSRT and response time variabil- magnetic resonance imaging studies of response inhibition dem- ity, we sought to understand the relationship between these vari- onstrate effects of both drugs on prefrontal activity Dopa- ables with correlation. No significant correlations were found be- mine, however, might play an important neuromodulatory role tween SSRT and response time variability in any of the drug within the basal ganglia, acting to transform the top-down inputs conditions, suggesting that these processes are largely indepen- into a focused, context-dependent signal that is able to suppress or dent (MPH: r ϭ .08, p Ͼ .05; ATM: r ϭ .02, p Ͼ .05; CIT: r ϭ .27, p Ͼ .05; facilitate behavior via the appropriate balance of activity within the PLAC: r ϭ .32, p Ͼ .05).
indirect or direct pathways, respectively Future studies shouldattempt to modulate SSRT with selective D1/D2 agonists or antag- Discussion
onists as well as with a broader range of cognitive tasks to accu- This study demonstrated that clinically relevant doses of MPH rately reflect the complexity and breadth of the construct of inhibi- were able to reduce SSRT and behavioral variability without con- comitant changes in response speed or accuracy of responding.
Recent evidence from ADHD suggests that response time vari- The inability of CIT to facilitate action cancelation is consistent with ability and inhibition load onto distinct, familial cognitive factors other human studies However, the failure to confirm a beneficial with the former potentially linked to diminished arousal and effect of ATM compared with PLAC on SSRT contrasts with other drifting attention and the latter linked to executive processes.
work in humans and rodents Our results challenge the view Interestingly, although both stop-signal reaction time and re- that stimulant medications act to solely speed motoric processes sponse time variability were robustly improved by MPH in the cur- without specific effects on action cancelation rent study, these measures were largely uncorrelated in each of the drug conditions, providing further evidence that they are poten- 6. Johnson KA, Kelly SP, Bellgrove MA, Barry E, Cox M, Gill M, Robertson IH (2007): Response variability in attention deficit hyperactivity disorder: Chamberlain et al. reported that an acute dose of ATM 40 mg Evidence for neuropsychological heterogeneity. Neuropsychologia 45: reduced SSRT compared with PLAC. A comparison of the effect size associated with the ATM versus PLAC difference in Chamberlain et 7. Chamberlain SR, Muller U, Blackwell AD, Clark L, Robbins TW, Sahakian BJ (2006): Neurochemical modulation of response inhibition and prob- al. and the current study revealed Cohen’s d effect sizes of .37 and abilistic learning in humans. Science 311:861– 863.
.32, respectively. Because these effect sizes are modest, non-repli- 8. Bari A, Eagle DM, Mar AC, Robinson ES, Robbins TW (2009): Dissociable cations are likely. It is also notable that the PLAC condition of the effects of noradrenaline, dopamine, and serotonin uptake blockade on current study yielded comparable results (Chamberlain: SSRT: 278 stop task performance in rats. Psychopharmacology (Berl) 205:273–283.
msec; Nandam et al.: SSRT: 275 msec), suggesting that baseline 9. Chamberlain SR, Hampshire A, Muller U, Rubia K, Campo ND, Craig K, et differences between the studies are unlikely to account for this al. (2008): Atomoxetine modulates right inferior frontal activation dur- non-replication. Participant factors such as DNA variation in the NET ing inhibitory control: A pharmacological functional magnetic reso- genes might also account for the weaker effect of ATM in the nance imaging study. Biol Psychiatry 65:550 –555.
10. Eagle DM, Bari A, Robbins TW (2008): The neuropsychopharmacology of action inhibition: Cross-species translation of the stop-signal and go/ Although we found strong evidence that MPH specifically im- no-go tasks. Psychopharmacology (Berl) 199:439 – 456.
proved response inhibition and response time variability, we found 11. Volkow ND, Wang G, Fowler JS, Logan J, Gerasimov M, Maynard L, et al. no significant change compared with PLAC for ATM. Our results (2001): Therapeutic doses of oral methylphenidate significantly in- provide foundational data that might help to explain why acute crease extracellular dopamine in the human brain. J Neurosci 21:RC121.
doses of MPH have therapeutic value in disorders such as ADHD.
12. Berridge CW, Devilbiss DM, Andrzejewski ME, Arnsten AF, Kelley AE, Schmeichel B, et al. (2006): Methylphenidate preferentially increases This work was supported by grants from the Australian Research catecholamine neurotransmission within the prefrontal cortex at low Council (DP0770337) to MAB and from the Australian National Health doses that enhance cognitive function. Biol Psychiatry 60:1111–1120.
13. Bymaster FP, Katner JS, Nelson DL, Hemrick-Luecke SK, Threlkeld PG, and Medical Research Council to MAB, RLH, PJN, and JBM. We would Heiligenstein JH, et al. (2002): Atomoxetine increases extracellular levels like to thank Dr. Chris Chambers for comments on the manuscript. We of norepinephrine and dopamine in prefrontal cortex of rat: A potential would also like to thank the Wesley Hospital Pharmacy for dispensing mechanism for efficacy in attention deficit/hyperactivity disorder. Neu- the drugs associated with this project. ropsychopharmacology 27:699 –711.
Both LSN and MAB have received reimbursement from Lilly Phar- 14. Arnsten AF, Dudley AG (2005): Methylphenidate improves prefrontal maceuticals for conference travel expenses and for speaking at confer- cortical cognitive function through alpha2 adrenoceptor and dopa- ences. The authors MAB and B-NK have received speaker’s fees from mine D1 receptor actions: Relevance to therapeutic effects in attention Jannsen Cilag. The author LSN has received speaker’s fees from Bristol- deficit hyperactivity disorder. Behav Brain Funct 1:2.
Myers Squibb, Boehringer, and Janssesn Cilag. The authors RH, JW, 15. Aron AR, Poldrack RA (2006): Cortical and subcortical contributions to TDRC, KG, AJD, PJN, and JBM report no biomedical financial interests or stop signal response inhibition: Role of the subthalamic nucleus. J Neu-rosci 26:2424 –2433.
16. Chambers CD, Garavan H, Bellgrove MA (2009): Insights into the neural Supplementary material cited in this article is available online. basis of response inhibition from cognitive and clinical neuroscience.
Neurosci Biobehav Rev 33:631– 646.
17. Vaidya CJ, Bunge SA, Dudukovic NM, Zalecki CA, Elliott GR, Gabrieli JD 1. Bellgrove MA, Chambers CD, Vance A, Hall N, Karamitsios M, Bradshaw (2005): Altered neural substrates of cognitive control in childhood JL (2006): Lateralized deficit of response inhibition in early-onset schizo- ADHD: Evidence from functional magnetic resonance imaging. Am J phrenia. Psychol Med 36:495–505.
2. Menzies L, Achard S, Chamberlain SR, Fineberg N, Chen CH, del Campo 18. Mink JW (1996): The basal ganglia: Focused selection and inhibition of N, et al. (2007): Neurocognitive endophenotypes of obsessive-compul-sive disorder. Brain 130:3223–3236.
competing motor programs. Prog Neurobiol 50:381– 425.
3. Lijffijt M, Kenemans JL, Verbaten MN, van Engeland H (2005): A meta- 19. Kuntsi J, Wood AC, Rijsdijk F, Johnson KA, Andreou P, Albrecht B, et al. analytic review of stopping performance in attention-deficit/hyperac- (2010): Separation of cognitive impairments in attention-deficit/hyper- tivity disorder: Deficient inhibitory motor control? J Abnorm Psychol activity disorder into 2 familial factors. Arch Gen Psychiatry 67:1159 – 4. Logan GD, Schachar RJ, Tannock R (1997): Impulsivity and inhibitory 20. Ramoz N, Boni C, Downing AM, Close SL, Peters SL, Prokop AM, et al. control. Psychol Sci 8:60 – 64.
(2009): A haplotype of the norepinephrine transporter (Net) gene 5. Bellgrove MA, Hester R, Garavan H (2004): The functional neuroanatomi- Slc6a2 is associated with clinical response to atomoxetine in attention- cal correlates of response variability: Evidence from a response inhibi- deficit hyperactivity disorder (ADHD). Neuropsychopharmacology 34: tion task. Neuropsychologia 42:1910 –1916.

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