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Citalopram Improves Response Inhibitionin more severe Parkinson’s DiseaseZheng Ye, Trevor Robbins, Ellemarije Altena, Char...
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Citalopram improves response inhibition in more severe Parkinson’s disease

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Presented in the Impulse Control Disorders in Parkinson's Disease meeting of the Movement Disorder Society (Boston, 2012)

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Citalopram improves response inhibition in more severe Parkinson’s disease

  1. 1. Citalopram Improves Response Inhibitionin more severe Parkinson’s DiseaseZheng Ye, Trevor Robbins, Ellemarije Altena, Charlotte Housden, Timothy Rittman,Cristina Nombela-Otero, James RoweUniversity of Cambridge, United Kingdom.More info: James.Rowe@mrc-cbu.cam.ac.uk (Dr. J. Rowe) or zy250@medschl.cam.ac.uk (Dr. Z. Ye)MethodsParticipants• PD patients (N = 21; three sessions): 10 females; right handed.• Healthy controls (N = 20; one session): 8 females; right handed; nohistory of neurological or psychiatric disorders.Table 1: Demographics of patients and controls (means , SDs and pvalues)BackgroundParkinson’s disease (PD) is characterized by cell loss of neuromodulatoryprojections from the brainstem to cortex and striatum, includingserotonin (5HT) and noradrenaline (NA) in addition to dopamine.Dopaminergic treatment, although relieving motor syndromes, hasbeen observed to impair behaviour control and increase impulsivity inearly PD (Cools et al. 2003). In health, both serotonin andnoradrenaline also modulate the neural systems for motor inhibitionimpulsivity (Chamberlain et al 2006, 2009; Macoveanu et al., in press).However, the roles of serotonergic and noradrenergic systems in PDimpulsivity are less well understood.This study investigated whether serotonergic and noradrenergictreatments enhance motor response inhibition, using a hybrid Stop-Signal and NoGo (SNG) task. By combining the classical NoGo andStop-Signal Reaction Time (SSRT) paradigms, the new task enables usto compare action restraint (the inhibition of action before it is made;NoGo) and action cancellation (the inhibition of action after it isinitiated; Stop-signal) in a single session at the same drug level. Wehave previously shown that individuals’ performances and regionalbrain activations in the new hybrid task are highly correlated withtheir performance when the NoGo and Stop-signal tasks are performedseparately (unpublished data). Here we tested two specific hypothesis.Hypothesis1: Action restraint (NoGo) and cancellation (SSRT) are bothimpaired in PD, more so with advanced disease.Hypothesis2: Action restraint impairments are influenced by serotonergictherapy (citalopram) while action cancellation deficits are modulatedby noradrenergic therapy (atomoxetine).References and FundingChamberlain et al. 2007. Biol Psychiatry 62(9): 977-84. Cools et al. 2001.Cereb Cortex 11(12): 1136-43. Cools et al. 2003. Neuropsychologia41(11): 1431-41. Logan & Cowan. 1984. Psychol Rev 91 (3): 295-327.This work was supported by the Wellcome Trust {088324}, MedicalResearch Council and the NIHR Biomedical Research Centre.ConclusionThis study examined two hypotheses regarding the roles of serotonergicand noradrenergic systems in response inhibition. The results indicate:For Hypothesis1: Action cancellation (SSRT) is impaired in PD.For Hypothesis2: Both action cancellation (SSRT) and restraint (NG)impairments were modulated by serotonergic treatment (citalopram)although not by the noradrenergic therapy (atomoxetine) in thesesubjects. The potential benefit of citalopram emerged with increasedseverity of Parkinsons diseaseDrugs and Design• Patients were tested under placebo (PLA), atomoxetine (ATO) andcitalopram (CIT) conditions in three different sessions (at least 6 daysapart) with a randomized double-blinded crossover design.• Atomoxetine (40 mg): a selective noradrenergic reuptake inhibitor thatincreases frontal cortical noradrenaline ~3 fold• Citalopram (30 mg): a highly specific serotonin reuptake inhibitor thatincreases extracellular cortical serotonin 2-4 foldTask and Stimuli• In each session there were 360 Go trials (75%), 40 NoGo trials (NG,8%) and 80 Stop-Signal trials (SS, 17%; approx 50% successful stop).• Go: Subjects responded to a left/right black arrow on screen bypressing left/right button (with right hand).• NG: To a red left/right cue and beep, subjects withheld an action.• SS: Manual button press response was cued by the left/right arrow butsignaled to stop by an auditory tone and colour change (to red) after avariable delay. An online tracking algorithm was maintainedconvergence on 50% successful cancellation (Chamberlain et al. 2007).Items Patients Controls P (2-tailed)Age (years) 64.00 (7.94) 65.30 (5.51) nsEducation (years) 14.57 (3.75) 15.05 (2.42) nsMMSE 28.86 (1.21) 29.30 (0.90) nsBDI 10.42 (4.92) 3.80 (3.80) <.001UPDRS (motor) 20.63 (7.67) -- --ResultsGroup effect (Hypothesis 1: controls vs. patients under PLA) and Drugeffect (Hypothesis 2: patients under PLA vs. ATO vs. CIT) wereexamined with two-sample t-tests (1-tailed) and repeat-measuresANOVAs respectively (Table 2). SSRT was calculated with theintegration method (Logan & Cowan 1984) and corrected forindividuals’ Go omission rates. NG error rate (NGRe) was alsocorrected according to omission rate.Group effects• Patients under PLA tended to be slower than controls in SSRT althoughthey were equally fast as controls in Go trials (GoRT).• More errors were observed for patients than controls in Go trials(GoRe) but not in NG trials (NGRe).Drug effects• There were no main effects of Drug (table 2)• However, new ANOVAs included disease severity (UPDRS) as acovariate. The new models confirmed interactions between the Drugand UPDRS (as covariate) for SSRT (F = 3.73, p < 0.05) and for NGRe (F= 2.86, p = 0.08). Specifically, there were correlations between theUPDRS and changes in SSRT, as well as between the UPDRS andchanges in NGRe (p<0.05: figure 2).• For CIT vs. PLA, both SSRT and NGRe differences were negativelycorrelated with UPDRS (Figure 1).• However this pattern was not obtained for ATO vs. PLA.Table 2: Group and drug effect (means, SDs and p values)Para-metersControlsPatientsPLAPatientsATOPatientsCITGroup(p value)Drug(p value)SSRT(ms)143(45)166(52)184(87)177(76).060 nsNGRe(%)1.63(5.02)3.59(3.84)3.77(6.70)5.21(8.74).10 nsGoRT(ms)532(129)557(110)557(105)559(103)ns nsGoRe(%)0.78(0.76)2.15(1.56)2.49(1.91)2.12(2.33)<.001 nsNGReCIT–PLASSRTCIT–PLA(ms)UPDRS (motor) UPDRS (motor)Figure 2: Negative correlations between UPDRS and SSRT/NGRedifferences under CIT vs. PLA

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